SHANGHAI, China, Feb. 20, 2023 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (“Junshi Biosciences”, HKEX: 1877; SSE: 688180) today announced that the pre-specified interim analysis has been completed for a randomized, double-blind, placebo-controlled, multi-center phase III clinical study (“TORCHLIGHT Study”, NCT04085276) examining the company’s product toripalimab in combination with paclitaxel for injection (albumin-bound) in patients with an initial diagnosis of stage IV or recurrent/metastatic triple-negative breast cancer. The Independent Data Monitoring Committee (IDMC) has determined that the primary endpoint met the pre-defined efficacy boundary. Junshi Biosciences will communicate with the regulatory authorities regarding matters related to the supplemental new drug application in the near future.

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Junshi Biosciences Announces Toripalimab in Combination with Chemotherapy for Treatment of Advanced Triple-negative Breast Cancer Met Primary Endpoint...

Advantages of IPS display panels:

If youve ever begun searching for a new computer screen, chances are youve probably come across the term IPS. Its at this point that you may be asking yourself,what is an IPS monitor?Andhow do I know if an IPS monitor is right for me?

To answer these questions we must first understand two things:

So, why is this important? A monitors panel technology is important because it affectswhat the monitor can doandfor which uses it is best suited.Each of the monitor panel types listed above offer their own distinctive benefits and drawbacks.

Choosing which type of monitor panel type to buy will depend largely on your intended usage and personal preference.After all, gamers, graphic designers, and office workers all have different requirements. Specific types of displays are best suited for different usage scenarios.

The specific type of LCD panel affects many different aspects of screen performance including:

Different panel technologies offer unique profiles with opinions on thebesttype of LCD being subjective and based on personal preference.

The reason for this is because none of the different monitor panel types as they are today can be classified as outstanding forallof the attributes mentioned above.

Below well take a look at how IPS, TN, and VA monitors affect screen performance and do some handy summaries of strengths, weaknesses, and best-case uses for each type of panel technology.

IPS monitors or In-Plane Switching monitors, leverage liquid crystals aligned in parallel to produce rich colors. IPS panels are defined by the shifting patterns of their liquid crystals. These monitors were designed to overcome the limitations of TN panels. The liquid crystals ability to shift horizontallycreates better viewing angles.

IPS monitors continue to be the display technology of choice for users that wantcolor accuracy and consistency. IPS monitors are really great when it comes tocolor performanceandsuper-wide viewing angles. The expansive viewing angles provided by IPS monitors help to deliver outstanding color when being viewed from different angles. One major differentiator between IPS monitors and TN monitors is that colors on an IPS monitor wont shift when being viewed at an angle as drastically as they do on a TN monitor.

IPS monitor variations include S-IPS, H-IPS, e-IPS and P-IPS, and PLS (Plane-to-Line Switching), the latter being the latest iteration. Since these variations are all quite similar, they are all collectively referred to as IPS-type panels. They all claim to deliver the major benefits associated with IPS monitors great color and ultra-wide viewing angles.

When it comes to color accuracy, IPS monitors surpass the performance of TN and VA monitors with ease. While latest-gen VA technologies offer comparative performance specs, pro users still claim thatIPS monitors reign supremein this regard.

Another important characteristic of IPS monitors is that they are able to support professional color space technologies, such asAdobe RGB. This is due to the fact that IPS monitors are able to offer more displayable colors, which help improve color accuracy.

In the past, response time and contrast were the initial weakness of IPS technology. Nowadays, however, IPS monitor response times have advanced to the point where they are even capable of satisfying gamers, thus resulting in a rising popularity inIPS monitors for gaming.

With regard to gaming, some criticisms IPS monitors include more visible motion blur coming as a result of slower response times, however the impact of motion blur will vary from user to user. In fact, mixed opinions about the drawbacks of IPS monitor for gaming can be found all across the web. Take this excerpt from one gaming technology writer for example: As for pixel response, opinions vary. I personally think IPS panels are quick enough for almost all gaming. If your gaming life is absolutely and exclusively about hair-trigger shooters, OK, youll want the fastest response, lowest latency LCD monitor. And that means TN. For the rest of us, and certainly for those who place even a modicum of importance on the visual spectacle of games, I reckon IPS is clearly the best panel technology. Read the full articlehere.

IPS monitors deliver ultra-wide 178-degree vertical and horizontal viewing angles. Graphic designers, CAD engineers, pro photographers, and video editors will benefit from using an IPS monitor. Many value the color benefits of IPS monitors and tech advances have improved IPS panel speed, contrast, and resolution. IPS monitors are more attractive than ever for general desktop work as well as many types of gaming. Theyre even versatile enough to be used in different monitor styles, so if youve ever compared an ultrawide vs. dual monitorsetup or considered the benefits ofcurved vs. flat monitors, chances are youve already come into contact with an IPS panel.

IPS Monitor Advantages:

IPS Monitor Drawbacks:

IPS Monitor Best Uses:

TN monitors, or Twisted Nematic monitors, are the oldest LCD panel types around. TN panels cost less than their IPS and VA counterparts and are a popular mainstream display technology for desktop and laptop displays.

Displays based on this monitor panel technology are ideal for cost-conscious consumers and entry-level multipurpose use.

Despite their lower perceived value, TN-based displays are the panel typepreferred by competitive gamers. The reason for this is because TN panels can achieve arapid response timeand thefastest refresh rates on the market(like this240Hz eSports monitor). To this effect, TN monitors are able toreduce blurring and screen tearingin fast-paced games when compared to an IPS or VA panel.

On the flip side,however, TN panel technology tends to be ill-suited for applications that benefit from wider viewing angles, higher contrast ratios, and better color accuracy. That being said, LED technology has helped shift the perspective and todays LED-backlit TN models offer higher brightness along with better blacks and higher contrast ratios.

The greatest constraint of TN panel technology, however, is a narrower viewing angle as TN monitors experience more color shifting than other types of panels when being viewed at an angle.

Todays maximum possible viewing angles are 178 degrees both horizontally and vertically (178/178), yet TN panels are limited to viewing angles of approximately 170 degrees horizontal and 160 degrees vertical (170 /160).

In fact, TN monitor can sometimes be easily identified by the color distortion and contrast shifting thats visible at the edges of the screen. As screen sizes increase, this issue becomes even more apparent as reduced color performance can even begin to be seen when viewing the screen from a dead-center position.

For general-purpose use, these shifts in color and contrast are often irrelevant and fade from conscious perception. However, this color variability makes TN monitors a poor choice for color-critical work like graphic design and photo editing. Graphic designers and other color-conscious users should also avoid TN displays due to their more limited range of color display compared to the other technologies.

TN monitors are the least expensive panel technology, making them ideal for cost-conscious businesses and consumers. In addition, TN monitors enjoy unmatched popularity with competitive gamers and other users who seek rapid graphics display.

TN Monitor Advantages:

TN Monitor Drawbacks:

TN Monitor Best Uses:

Vertical alignment (VA) panel technology was developed to improve upon the drawbacks of TN. Current VA-based monitors offer much higher contrast, better color reproduction, and wider viewing angles than TN panels. Variations you may see include P-MVA, S-MVA, and AMVA (Advanced MVA).

These high-end VA-type monitors rival IPS monitors as the best panel technology for professional-level color-critical applications. One of the standout features of VA technology is that it is particularly good at blocking light from the backlight when its not needed. This enables VA panels to display deeper blacks and static contrast ratios of up to several times higher than the other LCD technologies. The benefit of this is that VA monitors with high contrast ratios can deliver intense blacks and richer colors.

Contrast ratio is themeasured difference between the darkest blacks and the brightest whites a monitor can produce. This measurement provides information about the amount of grayscale detail a monitor will deliver. The higher the contrast ratio, the more visible detail.

These monitors also provide more visible details in shadows and highlights, making them ideal for enjoying videos and movies. Theyre also a good fit for games focused on rich imagery (RPG games for example) rather than rapid speed (such as FPS games).

MVA and other recent VA technologies offer the highest static contrast ratios of any panel technology. This allows for an outstanding visual experience for movie enthusiasts and other users seeking depth of detail. Higher-end, feature-rich MVA displays offer the consistent, authentic color representation needed by graphic designers and other pro users.

VA Monitor Advantages:

VA Monitor Drawbacks:

VA Monitor Best uses:

How does OLED compare to LCD?

There is another type of panel technology that differs from the monitor types discussed above and that is OLED or Organic Light Emitting Diode technology. OLEDs differ from LCDs because they use positively/negatively charged ions to light up every pixel individually, while LCDs use a backlight, which can create an unwanted glow. OLEDs avoid screen glow (and create darker blacks) by not using a backlight. One of the drawbacks of OLED technology is that it is usually pricier than any of the other types of technology explained.

Choosing the Right LCD Panel Technology

When it comes to choosing the right LCD panel technology, there is no single right answer. Each of the three primary technologies offers distinct strengths and weaknesses. Looking at different features and specs helps you identify which monitor best fits your needs.

With the lowest cost and fastest response times, TN monitors are great for general use and gaming. VA monitor offers a step up for general use. Maxed-out viewing angles and high contrast ratios make VA monitors great for watching movies and image-intensive gaming.

IPS monitors offer the greatest range of color-related features and remain the gold standard for photo editing and color-critical pro uses. Greater availability and lower prices make IPS monitors a great fit for anyone who values outstanding image quality.

LCD or Liquid Crystal Display is a type of monitor panel that embraces thin layers of liquid crystals sandwiched between two layers of filters and electrodes.

While CRT monitors used to fire electrons against glass surfaces, LCD monitors operate using backlights and liquid crystals. The LCD panel is a flat sheet of material that contains layers of filters, glass, electrodes, liquid crystals, and a backlight. Polarized light (meaning only half of it shines through) is directed towards a rectangular grid of liquid crystals and beamed through.

Liquid Crystals (LCs) are used because of their unique ability to maintain a parallel shape. Acting as both a solid and liquid, LCs are able to react quickly to changes in light patterns. The optical properties of LCs are activated by electric current, which is used to switch liquid crystals between phases. In turn, each pixel generates an RGB (red, green, blue) color based on the phase its in.

Note: When searching for monitors you can be sure to come across the term LED Panel at some point or another. An LED panel is an LCD screen with an LED (Light Emitting Diode) backlight. LEDs provide a brighter light source while using much less energy. They also have the ability to produce white color, in addition to traditional RGB color, and are the panel type used in HDR monitors.

Early LCD panels usedpassive-matrix technologyand were criticized for blurry imagery. The reason for this is because quick image changes require liquid crystals to change phase quickly and passive matrix technology was limited in terms of how quickly liquid crystals could change phase.

As a result,active-matrix technologywas invented andtransistors(TFTs) began being used to help liquid crystals retain their charge and change phase more quickly.

Thanks to active-matrix technology,LCD monitor panels were able to change images very quickly and the technology began being used by newer LCD panels.

Ultimately, budget and feature preferences will determine the best fit for each user. Among the available monitors of each panel type there will also be a range of price points and feature sets. Additionally, overall quality may vary among manufacturers due to factors related to a displays components, manufacturing, and design.

If youre interested in learning more about IPS monitors, you can take a look at some of theseprofessional monitorsto see if they would be the right fit for you.

Alternatively, if youre into gaming and are in the market for TN panel thesegaming monitoroptions may be along the lines of what youre looking for.

More:
What is an IPS Monitor? Monitor Panel Types Explained ...

IPS (in-plane switching) is a screen technology for liquid-crystal displays (LCDs). In IPS, a layer of liquid crystals is sandwiched between two glass surfaces. The liquid crystal molecules are aligned parallel to those surfaces in predetermined directions (in-plane). The molecules are reoriented by an applied electric field, whilst remaining essentially parallel to the surfaces to produce an image. It was designed to solve the strong viewing angle dependence and low-quality color reproduction of the twisted nematic field effect (TN) matrix LCDs prevalent in the late 1980s.[1]

The TN method was the only viable technology for active matrix TFT LCDs in the late 1980s and early 1990s. Early panels showed grayscale inversion from up to down,[2] and had a high response time (for this kind of transition, 1ms is visually better than 5ms). In the mid-1990s new technologies were developedtypically IPS and Vertical Alignment (VA)that could resolve these weaknesses and were applied to large computer monitor panels.

One approach patented in 1974 was to use inter-digitated electrodes on one glass substrate only to produce an electric field essentially parallel to the glass substrates.[3][4] However, the inventor was not yet able to implement such IPS-LCDs superior to TN displays.

After thorough analysis, details of advantageous molecular arrangements were filed in Germany by Guenter Baur et al. and patented in various countries including the US on 9 January 1990.[5][6] The Fraunhofer Society in Freiburg, where the inventors worked, assigned these patents to Merck KGaA, Darmstadt, Germany.

Shortly thereafter, Hitachi of Japan filed patents to improve this technology. A leader in this field was Katsumi Kondo, who worked at the Hitachi Research Center.[7] In 1992, engineers at Hitachi worked out various practical details of the IPS technology to interconnect the thin-film transistor array as a matrix and to avoid undesirable stray fields in between pixels.[8][9] Hitachi also improved the viewing angle dependence further by optimizing the shape of the electrodes (Super IPS). NEC and Hitachi became early manufacturers of active-matrix addressed LCDs based on the IPS technology. This is a milestone for implementing large-screen LCDs having acceptable visual performance for flat-panel computer monitors and television screens. In 1996, Samsung developed the optical patterning technique that enables multi-domain LCD. Multi-domain and in-plane switching subsequently remain the dominant LCD designs through 2006.[10]

Later, LG Display and other South Korean, Japanese, and Taiwanese LCD manufacturers adapted IPS technology.

IPS technology is widely used in panels for TVs, tablet computers, and smartphones. In particular, most IBM products was marketed as Flexview from 2004 to 2008 has an IPS LCDs with CCFL backlighting, and all Apple Inc. products marketed with the label Retina Display[11][12] feature IPS LCDs with LED backlighting since 2010.

In this case, both linear polarizing filters P and A have their axes of transmission in the same direction. To obtain the 90 degree twisted nematic structure of the LC layer between the two glass plates without an applied electric field (OFF state), the inner surfaces of the glass plates are treated to align the bordering LC molecules at a right angle. This molecular structure is practically the same as in TN LCDs. However, the arrangement of the electrodes e1 and e2 is different. Because they are in the same plane and on a single glass plate, they generate an electric field essentially parallel to this plate. The diagram is not to scale: the LC layer is only a few micrometers thick and so is very small compared with the distance between the electrodes.

The LC molecules have a positive dielectric anisotropy and align themselves with their long axis parallel to an applied electrical field. In the OFF state (shown on the left), entering light L1 becomes linearly polarized by polarizer P. The twisted nematic LC layer rotates the polarization axis of the passing light by 90 degrees, so that ideally no light passes through polarizer A. In the ON state, a sufficient voltage is applied between electrodes and a corresponding electrical field E is generated that realigns the LC molecules as shown on the right of the diagram. Here, light L2 can pass through polarizer A.

In practice, other schemes of implementation exist with a different structure of the LC molecules for example without any twist in the OFF state. As both electrodes are on the same substrate, they take more space than TN matrix electrodes. This also reduces contrast and brightness.[16]

Super-IPS was later introduced with better response times and colour reproduction.[17][unreliable source?]

Toward the end of 2010 Samsung Electronics introduced Super PLS (Plane-to-Line Switching) with the intent of providing an alternative to the popular IPS technology which is primarily manufactured by LG Display. It is an "IPS-type" panel technology, and is very similar in performance features, specs and characteristics to LG Display's offering. Samsung adopted PLS panels instead of AMOLED panels, because in the past AMOLED panels had difficulties in realizing full HD resolution on mobile devices. PLS technology was Samsung's wide-viewing angle LCD technology, similar to LG Display's IPS technology.[24]

Samsung asserted the following benefits of Super PLS (commonly referred to as just "PLS") over IPS:[25]

In 2012 AU Optronics began investment in their own IPS-type technology, dubbed AHVA. This should not be confused with their long standing AMVA technology (which is a VA-type technology). Performance and specs remained very similar to LG Display's IPS and Samsung's PLS offerings. The first 144Hz compatible IPS-type panels were produced in late 2014 (used first in early 2015) by AUO, beating Samsung and LG Display to providing high refresh rate IPS-type panels.[26][27]

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IPS panel - Wikipedia

Karina Hernandez, a nurse, mother and wife of a military officer, was diagnosed with cancer.

SAN ANTONIO A bone marrow registry was held Sunday for the wife of an Air Force Major stationed here in San Antonio.

Karina Hernandez, a nurse at BAMC, mother and wife of a military officer, was diagnosed with a rare bone marrow cancer called Myelofibrosis back in 2017 while pregnant.

She had severe pain in her side that wouldn't go away. Testing revealed that not only was she pregnant, she had an enlarged spleen due to Myelofibrosis.

We spoke with her awesome husband, Major Jesse Hernandez on Sunday about the challenges they have faced.

"Her cancer has progressed to the point where she know requires a bone marrow transplant in order to save her life," said Major Hernandez. "So today we're running a bone marrow registry drive with the goal to find a match for my wife and maybe for other patients who are facing the same need."

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There are over 18,000 patients that could benefit from healthy bone marrow and it could save their life.

"Karina continues to work at BAMC caring for other people, all while battling cancer," said Major Hernandez. "She has been on chemo medications the whole time and this is my opportunity to try and help her and hopefully find someone who is a match to help her."

Her friends and family all say Karina cares more about getting people to sign up for the registry to help others.

She is concerned that - It's not just for herself, it's for how many other people can be helped by this, said Dora Lopez, one of the drives organizers.

Unfortunately, Hispanics do not commonly sign themselves up as donors, said her family. So it has been difficult to try and find a match for her.

"The chances of a Caucasian patient finding a matches is 79% Hispanics is a 48% chance and African Americans is only a 29% chance," said Be The Match Recruitment Coordinator Melinda Dixon.

A bone marrow registry in her honor was held Sunday at St. Anthony Mary Claret Catholic Church located at 6150 Roft Road from 7 a.m. to 7 p.m.

If you missed the drive, you can still sign up for the registry by following this link or by texting Cure4Karina to 61474.

You must be at least 18 years old to register. You will not be asked to donate right away, only to swab the inside of your cheeks to send in so your DNA can be added to the national registry. if it is a match for a patient, a donation could save a life.

Since going on the air in 1950, KENS 5has strived to be the best, most trusted news and entertainment source for generations of San Antonians.

KENS 5 has brought numerous firsts to South Texas television, including being the first local station with a helicopter, the first with its own Doppler radar and the first to air a local morning news program.

Over the years, KENS 5 has worked to transform local news. Our cameras have been the lens bringing history into local viewers' homes. We're proud of our legacy as we serve San Antonians today.

Today, KENS 5 continues to set the standard in local broadcasting and is recognized by its peers for excellence and innovation. The KENS 5 News team focuses on stories that really matter to our community.

You can find KENS 5 in more places than ever before, including KENS5.com, the KENS 5 app, the KENS 5 YouTube channel, KENS 5's Roku and Fire TV apps, and across social media on Facebook, Twitter, Instagram and more!

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Bone marrow drive held for military wife with cancer

Overview

Bone cancer can begin in any bone in the body, but it most commonly affects the pelvis or the long bones in the arms and legs. Bone cancer is rare, making up less than 1 percent of all cancers. In fact, noncancerous bone tumors are much more common than cancerous ones.

The term "bone cancer" doesn't include cancers that begin elsewhere in the body and spread (metastasize) to the bone. Instead, those cancers are named for where they began, such as breast cancer that has metastasized to the bone.

Some types of bone cancer occur primarily in children, while others affect mostly adults. Surgical removal is the most common treatment, but chemotherapy and radiation therapy also may be utilized. The decision to use surgery, chemotherapy or radiation therapy is based on the type of bone cancer being treated.

Signs and symptoms of bone cancer include:

Make an appointment with your doctor if you or your child develops bone pain that:

Subscribe for free and receive an in-depth guide to coping with cancer, plus helpful information on how to get a second opinion. You can unsubscribe at any time.

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The cause of most bone cancers is unknown. A small number of bone cancers have been linked to hereditary factors, while others are related to previous radiation exposure.

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Osteosarcoma, the most common type of bone cancer, often starts in the long bones the legs or the arms but it can occur in any bone.

Bone cancers are broken down into separate types based on the type of cell where the cancer began. The most common types of bone cancer include:

It's not clear what causes bone cancer, but doctors have found certain factors are associated with an increased risk, including:

Bone cancer care at Mayo Clinic

March 22, 2022

Connect with others like you for support and answers to your questions in the Cancer support group on Mayo Clinic Connect, a patient community.

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Bone cancer - Symptoms and causes - Mayo Clinic

Cynthias story

Cynthia had always been proud of her skin, especially her summer tan. But, as years went by, she saw her skin getting more fine lines and wrinkles. Cynthia began to worry about what other skin problems she might have. What were those brown spots on her hands and arms?

Your skin changes with age. It becomes thinner, loses fat, and no longer looks as plump and smooth as it once did. Your veins and bones can be seen more easily. Scratches, cuts, or bumps can take longer to heal. Years of suntanning or being out in the sunlight for a long time may lead to wrinkles, dryness, age spots, and even cancer. But there are things you can do to protect your skin and to make it feel and look better.

Many older people suffer from dry spots on their skin, often on their lower legs, elbows, and lower arms. Dry skin patches feel rough and scaly. There are many possible reasons for dry skin, such as:

Dry skin also can be caused by health problems, such as diabetes or kidney disease. Using too much soap, antiperspirant, or perfume and taking hot baths can make dry skin worse.

Some medicines can make skin itchy. Because older people have thinner skin, scratching can cause bleeding that may lead to infection. Talk to your doctor if your skin is very dry and itchy.

Here are some ways to help dry, itchy skin:

Older people may bruise more easily than younger people. It can take longer for these bruises to heal. Some medicines or illnesses may also cause bruising. Talk to your doctor if you see bruises and dont know how you got them, especially on parts of your body usually covered by clothing.

Over time, skin begins to wrinkle. Things in the environment, like ultraviolet (UV) light from the sun, can make the skin less elastic. Gravity can cause skin to sag and wrinkle. Certain habits, like smoking, also can wrinkle the skin.

A lot of claims are made about ways to make wrinkles go away. Most of them dont work. Some methods can be painful or even dangerous, and many must be done by a doctor. Talk with a doctor specially trained in skin problems, called a dermatologist, or your regular doctor if you are worried about wrinkles.

Age spots, once called liver spots, are flat, brown spots often caused by years in the sun. They are bigger than freckles and commonly show up on areas like the face, hands, arms, back, and feet. Using a broad-spectrum sunscreen that helps protect against two types of the suns rays (UVA and UVB) may prevent more age spots.

Skin tags are small, usually flesh-colored growths of skin that have a raised surface. They become common as people age, especially for women. They are most often found on the eyelids, neck, and body folds such as the armpit, chest, and groin.

Age spots and skin tags are harmless, although sometimes skin tags can become irritated. If your age spots or skin tags bother you, talk to your doctor about having them removed.

Skin cancer is a very common type of cancer in the United States. The main cause of skin cancer is the sun. Sunlamps and tanning booths can also cause skin cancer. Anyone, of any skin color, can get skin cancer. People with fair skin that freckles easily are at greatest risk. Skin cancer may be cured if it is found before it spreads to other parts of the body.

There are three types of skin cancers. Two types, basal cell carcinoma and squamous cell carcinoma, grow slowly and rarely spread to other parts of the body. These types of cancer are usually found on parts of the skin most often exposed to the sun, like the head, face, neck, hands, and arms. But they can happen anywhere on your body. The third and most dangerous type of skin cancer is melanoma. It is rarer than the other types, but it can spread to other organs and be deadly.

Check your skin once a month for things that may be signs of cancer. Skin cancer is rarely painful. Look for changes such as a new growth, a sore that doesnt heal, or a bleeding mole.

A = Asymmetry (one half of the growth looks different from the other half)

B = Borders that are irregular

C = Color changes or more than one color

D = Diameter greater than the size of a pencil eraser

E = Evolving; meaning the growth changes in size, shape, symptoms (itching, tenderness), surface (especially bleeding), or shades of color

See your doctor right away if you have any of these signs to make sure it is not skin cancer.

Some sun can be good for you, but to keep your skin healthy, be careful:

Your skin may change with age. But remember, there are things you can do to help. Check your skin often. If you find any changes that worry you, see your doctor.

Read about this topic in Spanish. Lea sobre este tema en espaol.

This content is provided by the NIH National Institute on Aging (NIA). NIA scientists and other experts review this content to ensure it is accurate and up to date.

Content reviewed: October 01, 2017

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Skin Care and Aging | National Institute on Aging

1 Growth at constant exchange rates and scope corresponds to organic growth of sales, excluding exchange rate variations, by calculating the indicator for the financial year in question and the indicator for the previous financial year on the basis of identical exchange rates (the exchange rate used is the previous financial year’s), and excluding change in scope, by calculating the indicator for the financial year in question on the basis of the scope of consolidation for the previous financial year.

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VIRBAC: Annual revenue growth of +9.6% at comparable exchange rates and scope (+14.3% at real rates), driven by exceptional business activity in the...

FORT LAUDERDALE, Fla., Jan. 10, 2023 (GLOBE NEWSWIRE) -- Motus GI Holdings, Inc., (NASDAQ: MOTS) (“Motus GI” or the “Company”), a medical technology company providing endoscopy solutions that improve clinical outcomes and enhance the cost-efficiency associated with the diagnosis and management of gastrointestinal conditions, announced today it has initiated a process to explore a range of strategic and financing alternatives focused on maximizing stockholder value and accelerating commercialization of the Pure-Vu System. As part of this process, the Company has engaged Lake Street Capital Markets LLC to act as an advisor to the Company in this process.

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Motus GI Announces Exploration of Strategic Alternatives to Enhance Shareholder Value and Announces Restructuring Plan

Topline data expected in the first half of 2023 Topline data expected in the first half of 2023

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Journey Medical Corporation Completes Enrollment in Phase 3 Clinical Trials Evaluating DFD-29 (Minocycline Modified Release Capsules 40 mg) for the...

Learning Objectives

By the end of this section, you will be able to:

The brain and the spinal cord are the central nervous system, and they represent the main organs of the nervous system. The spinal cord is a single structure, whereas the adult brain is described in terms of four major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum. A persons conscious experiences are based on neural activity in the brain. The regulation of homeostasis is governed by a specialized region in the brain. The coordination of reflexes depends on the integration of sensory and motor pathways in the spinal cord.

The iconic gray mantle of the human brain, which appears to make up most of the mass of the brain, is the cerebrum (Figure 14.3.1). The wrinkled portion is the cerebral cortex, and the rest of the structure is beneath that outer covering. There is a large separation between the two sides of the cerebrum called the longitudinal fissure. It separates the cerebrum into two distinct halves, a right and left cerebral hemisphere. Deep within the cerebrum, the white matter of the corpus callosum provides the major pathway for communication between the two hemispheres of the cerebral cortex.

Many of the higher neurological functions, such as memory, emotion, and consciousness, are the result of cerebral function. The complexity of the cerebrum is different across vertebrate species. The cerebrum of the most primitive vertebrates is not much more than the connection for the sense of smell. In mammals, the cerebrum comprises the outer gray matter that is the cortex (from the Latin word meaning bark of a tree) and several deep nuclei that belong to three important functional groups. The basal nuclei are responsible for cognitive processing, the most important function being that associated with planning movements. The basal forebrain contains nuclei that are important in learning and memory. The limbic cortex is the region of the cerebral cortex that is part of the limbic system, a collection of structures involved in emotion, memory, and behavior.

The cerebrum is covered by a continuous layer of gray matter that wraps around either side of the forebrainthe cerebral cortex. This thin, extensive region of wrinkled gray matter is responsible for the higher functions of the nervous system. A gyrus (plural = gyri) is the ridge of one of those wrinkles, and a sulcus (plural = sulci) is the groove between two gyri. The pattern of these folds of tissue indicates specific regions of the cerebral cortex.

The head is limited by the size of the birth canal, and the brain must fit inside the cranial cavity of the skull. Extensive folding in the cerebral cortex enables more gray matter to fit into this limited space. If the gray matter of the cortex were peeled off of the cerebrum and laid out flat, its surface area would be roughly equal to one square meter.

The folding of the cortex maximizes the amount of gray matter in the cranial cavity. During embryonic development, as the telencephalon expands within the skull, the brain goes through a regular course of growth that results in everyones brain having a similar pattern of folds. The surface of the brain can be mapped on the basis of the locations of large gyri and sulci. Using these landmarks, the cortex can be separated into four major regions, or lobes (Figure 14.3.2). The lateral sulcus that separates the temporal lobe from the other regions is one such landmark. Superior to the lateral sulcus are the parietal lobe and frontal lobe, which are separated from each other by the central sulcus. The posterior region of the cortex is the occipital lobe, which has no obvious anatomical border between it and the parietal or temporal lobes on the lateral surface of the brain. From the medial surface, an obvious landmark separating the parietal and occipital lobes is called the parieto-occipital sulcus. The fact that there is no obvious anatomical border between these lobes is consistent with the functions of these regions being interrelated.

Different regions of the cerebral cortex can be associated with particular functions, a concept known as localization of function. In the early 1900s, a German neuroscientist named Korbinian Brodmann performed an extensive study of the microscopic anatomythe cytoarchitectureof the cerebral cortex and divided the cortex into 52 separate regions on the basis of the histology of the cortex. His work resulted in a system of classification known as Brodmanns areas, which is still used today to describe the anatomical distinctions within the cortex (Figure 14.3.3). The results from Brodmanns work on the anatomy align very well with the functional differences within the cortex. Areas 17 and 18 in the occipital lobe are responsible for primary visual perception. That visual information is complex, so it is processed in the temporal and parietal lobes as well.

The temporal lobe is associated with primary auditory sensation, known as Brodmanns areas 41 and 42 in the superior temporal lobe. Because regions of the temporal lobe are part of the limbic system, memory is an important function associated with that lobe. Memory is essentially a sensory function; memories are recalled sensations such as the smell of Moms baking or the sound of a barking dog. Even memories of movement are really the memory of sensory feedback from those movements, such as stretching muscles or the movement of the skin around a joint. Structures in the temporal lobe are responsible for establishing long-term memory, but the ultimate location of those memories is usually in the region in which the sensory perception was processed.

The main sensation associated with the parietal lobe is somatosensation, meaning the general sensations associated with the body. Posterior to the central sulcus is the postcentral gyrus, the primary somatosensory cortex, which is identified as Brodmanns areas 1, 2, and 3. All of the tactile senses are processed in this area, including touch, pressure, tickle, pain, itch, and vibration, as well as more general senses of the body such as proprioception and kinesthesia, which are the senses of body position and movement, respectively.

Anterior to the central sulcus is the frontal lobe, which is primarily associated with motor functions. The precentral gyrus is the primary motor cortex. Cells from this region of the cerebral cortex are the upper motor neurons that instruct cells in the spinal cord and brain stem (lower motor neurons) to move skeletal muscles. Anterior to this region are a few areas that are associated with planned movements. The premotor area is responsible for storing learned movement algorithms which are instructions for complex movements. Different algorithmsactivate the upper motor neurons in the correct sequence when a complex motor activity is performed.The frontal eye fields are important in eliciting scanning eye movements and in attending to visual stimuli. Brocas area is responsible for the production of language, or controlling movements responsible for speech; in the vast majority of people, it is located only on the left side. Anterior to these regions is the prefrontal lobe, which serves cognitive functions that can be the basis of personality, short-term memory, and consciousness. The prefrontal lobotomy is an outdated mode of treatment for personality disorders (psychiatric conditions) that profoundly affected the personality of the patient.

Area 17, as Brodmann described it, is also known as the primary visual cortex. Adjacent to that are areas 18 and 19, which constitute subsequent regions of visual processing. Area 22 is the primary auditory cortex, and it is followed by area 23, which further processes auditory information. Area 4 is the primary motor cortex in the precentral gyrus, whereas area 6 is the premotor cortex. These areas suggest some specialization within the cortex for functional processing, both in sensory and motor regions. The fact that Brodmanns areas correlate so closely to functional localization in the cerebral cortex demonstrates the strong link between structure and function in these regions.

Areas 1, 2, 3, 4, 17, and 22 are each described as primary cortical areas. The adjoining regions are each referred to as association areas. Primary areas are where sensory information is initially received from the thalamus for conscious perception, orin the case of the primary motor cortexwhere descending commands are sent down to the brain stem or spinal cord to execute movements (Figure 14.3.4).

The cerebrum is the seat of many of the higher mental functions, such as memory and learning, language, and conscious perception, which are the subjects of subtests of the mental status exam. The cerebral cortex is the thin layer of gray matter on the outside of the cerebrum. It is approximately a millimeter thick in most regions and highly folded to fit within the limited space of the cranial vault. These higher functions are distributed across various regions of the cortex, and specific locations can be said to be responsible for particular functions. There is a limited set of regions, for example, that are involved in language function, and they can be subdivided on the basis of the particular part of language function that each governs.

A number of other regions, which extend beyond these primary or association areas of the cortex, are referred to as integrative areas. These areas are found in the spaces between the domains for particular sensory or motor functions, and they integrate multisensory information, or process sensory or motor information in more complex ways. Consider, for example, the posterior parietal cortex that lies between the somatosensory cortex and visual cortex regions. This has been ascribed to the coordination of visual and motor functions, such as reaching to pick up a glass. The somatosensory function that would be part of this is the proprioceptive feedback from moving the arm and hand. The weight of the glass, based on what it contains, will influence how those movements are executed.

Assessment of cerebral functions is directed at cognitive abilities. The abilities assessed through the mental status exam can be separated into four groups: orientation and memory, language and speech, sensorium, and judgment and abstract reasoning.

Orientation is the patients awareness of his or her immediate circumstances. It is awareness of time, not in terms of the clock, but of the date and what is occurring around the patient. It is awareness of place, such that a patient should know where he or she is and why. It is also awareness of who the patient isrecognizing personal identity and being able to relate that to the examiner. The initial tests of orientation are based on the questions, Do you know what the date is? or Do you know where you are? or What is your name? Further understanding of a patients awareness of orientation can come from questions that address remote memory, such as Who is the President of the United States?, or asking what happened on a specific date.

There are also specific tasks to address memory. One is the three-word recall test. The patient is given three words to recall, such as book, clock, and shovel. After a short interval, during which other parts of the interview continue, the patient is asked to recall the three words. Other tasks that assess memoryaside from those related to orientationhave the patient recite the months of the year in reverse order to avoid the overlearned sequence and focus on the memory of the months in an order, or to spell common words backwards, or to recite a list of numbers back.

Memory is largely a function of the temporal lobe, along with structures beneath the cerebral cortex such as the hippocampus and the amygdala. The storage of memory requires these structures of the medial temporal lobe. A famous case of a man who had both medial temporal lobes removed to treat intractable epilepsy provided insight into the relationship between the structures of the brain and the function of memory.

Henry Molaison, who was referred to as patient HM when he was alive, had epilepsy localized to both of his medial temporal lobes. In 1953, a bilateral lobectomy was performed that alleviated the epilepsy but resulted in the inability for HM to form new memoriesa condition called anterograde amnesia. HM was able to recall most events from before his surgery, although there was a partial loss of earlier memories, which is referred to as retrograde amnesia. HM became the subject of extensive studies into how memory works. What he was unable to do was form new memories of what happened to him, what are now called episodic memory. Episodic memory is autobiographical in nature, such as remembering riding a bicycle as a child around the neighborhood, as opposed to the procedural memory of how to ride a bike. HM also retained his short-term memory, such as what is tested by the three-word task described above. After a brief period, those memories would dissipate or decay and not be stored in the long-term because the medial temporal lobe structures were removed.

The difference in short-term, procedural, and episodic memory, as evidenced by patient HM, suggests that there are different parts of the brain responsible for those functions. The long-term storage of episodic memory requires the hippocampus and related medial temporal structures, and the location of those memories is in the multimodal integration areas of the cerebral cortex. However, short-term memoryalso called working or active memoryis localized to the prefrontal lobe. Because patient HM had only lost his medial temporal lobeand lost very little of his previous memories, and did not lose the ability to form new short-term memoriesit was concluded that the function of the hippocampus, and adjacent structures in the medial temporal lobe, is to move (or consolidate) short-term memories (in the pre-frontal lobe) to long-term memory (in the temporal lobe).

The prefrontal cortex can also be tested for the ability to organize information. In one subtest of the mental status exam called set generation, the patient is asked to generate a list of words that all start with the same letter, but not to include proper nouns or names. The expectation is that a person can generate such a list of at least 10 words within 1 minute. Many people can likely do this much more quickly, but the standard separates the accepted normal from those with compromised prefrontal cortices.

Read this article to learn about a young man who texts his fiance in a panic as he finds that he is having trouble remembering things. At the hospital, a neurologist administers the mental status exam, which is mostly normal except for the three-word recall test. The young man could not recall them even 30 seconds after hearing them and repeating them back to the doctor. An undiscovered mass in the mediastinum region was found to be Hodgkins lymphoma, a type of cancer that affects the immune system and likely caused antibodies to attack the nervous system. The patient eventually regained his ability to remember, though the events in the hospital were always elusive. Considering that the effects on memory were temporary, but resulted in the loss of the specific events of the hospital stay, what regions of the brain were likely to have been affected by the antibodies and what type of memory does that represent?

Language is, arguably, a very human aspect of neurological function. There are certainly strides being made in understanding communication in other species, but much of what makes the human experience seemingly unique is its basis in language. Any understanding of our species is necessarily reflective, as suggested by the question What am I? And the fundamental answer to this question is suggested by the famous quote by Ren Descartes: Cogito Ergo Sum (translated from Latin as I think, therefore I am). Formulating an understanding of yourself is largely describing who you are to yourself. It is a confusing topic to delve into, but language is certainly at the core of what it means to be self-aware.

The neurological exam has two specific subtests that address language. One measures the ability of the patient to understand language by asking them to follow a set of instructions to perform an action, such as touch your right finger to your left elbow and then to your right knee. Another subtest assesses the fluency and coherency of language by having the patient generate descriptions of objects or scenes depicted in drawings, and by reciting sentences or explaining a written passage. Language, however, is important in so many ways in the neurological exam. The patient needs to know what to do, whether it is as simple as explaining how the knee-jerk reflex is going to be performed, or asking a question such as What is your name? Often, language deficits can be determined without specific subtests; if a person cannot reply to a question properly, there may be a problem with the reception of language.

An important example of multimodal integrative areas is associated with language function (Figure 14.3.5). Adjacent to the auditory association cortex, at the end of the lateral sulcus just anterior to the visual cortex, is Wernickes area. In the lateral aspect of the frontal lobe, just anterior to the region of the motor cortex associated with the head and neck, is Brocas area. Both regions were originally described on the basis of losses of speech and language, which is called aphasia. The aphasia associated with Brocas area is known as an expressive aphasia, which means that speech production is compromised. This type of aphasia is often described as non-fluency because the ability to say some words leads to broken or halting speech. Grammar can also appear to be lost. The aphasia associated with Wernickes area is known as a receptive aphasia, which is not a loss of speech production, but a loss of understanding of content. Patients, after recovering from acute forms of this aphasia, report not being able to understand what is said to them or what they are saying themselves, but they often cannot keep from talking.

The two regions are connected by white matter tracts that run between the posterior temporal lobe and the lateral aspect of the frontal lobe. Conduction aphasia associated with damage to this connection refers to the problem of connecting the understanding of language to the production of speech. This is a very rare condition, but is likely to present as an inability to faithfully repeat spoken language.

Those parts of the brain involved in the reception and interpretation of sensory stimuli are referred to collectively as the sensorium. The cerebral cortex has several regions that are necessary for sensory perception. From the primary cortical areas of the somatosensory, visual, auditory, and gustatory senses to the association areas that process information in these modalities, the cerebral cortex is the seat of conscious sensory perception. In contrast, sensory information can also be processed by deeper brain regions, which we may vaguely describe as subconsciousfor instance, we are not constantly aware of the proprioceptive information that the cerebellum uses to maintain balance. Several of the subtests can reveal activity associated with these sensory modalities, such as being able to hear a question or see a picture. Two subtests assess specific functions of these cortical areas.

The first is praxis, a practical exercise in which the patient performs a task completely on the basis of verbal description without any demonstration from the examiner. For example, the patient can be told to take their left hand and place it palm down on their left thigh, then flip it over so the palm is facing up, and then repeat this four times. The examiner describes the activity without any movements on their part to suggest how the movements are to be performed. The patient needs to understand the instructions, transform them into movements, and use sensory feedback, both visual and proprioceptive, to perform the movements correctly.

The second subtest for sensory perception is gnosis, which involves two tasks. The first task, known as stereognosis, involves the naming of objects strictly on the basis of the somatosensory information that comes from manipulating them. The patient keeps their eyes closed and is given a common object, such as a coin, that they have to identify. The patient should be able to indicate the particular type of coin, such as a dime versus a penny, or a nickel versus a quarter, on the basis of the sensory cues involved. For example, the size, thickness, or weight of the coin may be an indication, or to differentiate the pairs of coins suggested here, the smooth or corrugated edge of the coin will correspond to the particular denomination. The second task, graphesthesia, is to recognize numbers or letters written on the palm of the hand with a dull pointer, such as a pen cap.

Praxis and gnosis are related to the conscious perception and cortical processing of sensory information. Being able to transform verbal commands into a sequence of motor responses, or to manipulate and recognize a common object and associate it with a name for that object. Both subtests have language components because language function is integral to these functions. The relationship between the words that describe actions, or the nouns that represent objects, and the cerebral location of these concepts is suggested to be localized to particular cortical areas. Certain aphasias can be characterized by a deficit of verbs or nouns, known as V impairment or N impairment, or may be classified as VN dissociation. Patients have difficulty using one type of word over the other. To describe what is happening in a photograph as part of the expressive language subtest, a patient will use active- or image-based language. The lack of one or the other of these components of language can relate to the ability to use verbs or nouns. Damage to the region at which the frontal and temporal lobes meet, including the region known as the insula, is associated with V impairment; damage to the middle and inferior temporal lobe is associated with N impairment.

Planning and producing responses requires an ability to make sense of the world around us. Making judgments and reasoning in the abstract are necessary to produce movements as part of larger responses. For example, when your alarm goes off, do you hit the snooze button or jump out of bed? Is 10 extra minutes in bed worth the extra rush to get ready for your day? Will hitting the snooze button multiple times lead to feeling more rested or result in a panic as you run late? How you mentally process these questions can affect your whole day.

The prefrontal cortex is responsible for the functions responsible for planning and making decisions. In the mental status exam, the subtest that assesses judgment and reasoning is directed at three aspects of frontal lobe function. First, the examiner asks questions about problem solving, such as If you see a house on fire, what would you do? The patient is also asked to interpret common proverbs, such as Dont look a gift horse in the mouth. Additionally, pairs of words are compared for similarities, such as apple and orange, or lamp and cabinet.

The prefrontal cortex is composed of the regions of the frontal lobe that are not directly related to specific motor functions. The most posterior region of the frontal lobe, the precentral gyrus, is the primary motor cortex. Anterior to that are the premotor cortex, Brocas area, and the frontal eye fields, which are all related to planning certain types of movements. Anterior to what could be described as motor association areas are the regions of the prefrontal cortex. They are the regions in which judgment, abstract reasoning, and working memory are localized. The antecedents to planning certain movements are judging whether those movements should be made, as in the example of deciding whether to hit the snooze button.

To an extent, the prefrontal cortex may be related to personality. The neurological exam does not necessarily assess personality, but it can be within the realm of neurology or psychiatry. A clinical situation that suggests this link between the prefrontal cortex and personality comes from the story of Phineas Gage, the railroad worker from the mid-1800s who had a metal spike impale his prefrontal cortex. There are suggestions that the steel rod led to changes in his personality. A man who was a quiet, dependable railroad worker became a raucous, irritable drunkard. Later anecdotal evidence from his life suggests that he was able to support himself, although he had to relocate and take on a different career as a stagecoach driver.

A psychiatric practice to deal with various disorders was the prefrontal lobotomy. This procedure was common in the 1940s and early 1950s, until antipsychotic drugs became available. The connections between the prefrontal cortex and other regions of the brain were severed. The disorders associated with this procedure included some aspects of what are now referred to as personality disorders, but also included mood disorders and psychoses. Depictions of lobotomies in popular media suggest a link between cutting the white matter of the prefrontal cortex and changes in a patients mood and personality, though this correlation is not well understood.

Popular media often refer to right-brained and left-brained people, as if the brain were two independent halves that work differently for different people. This is a popular misinterpretation of an important neurological phenomenon. As an extreme measure to deal with a debilitating condition, the corpus callosum may be sectioned to overcome intractable epilepsy. When the connections between the two cerebral hemispheres are cut, interesting effects can be observed.

If a person with an intact corpus callosum is asked to put their hands in their pockets and describe what is there on the basis of what their hands feel, they might say that they have keys in their right pocket and loose change in the left. They may even be able to count the coins in their pocket and say if they can afford to buy a candy bar from the vending machine. If a person with a sectioned corpus callosum is given the same instructions, they will do something quite peculiar. They will only put their right hand in their pocket and say they have keys there. They will not even move their left hand, much less report that there is loose change in the left pocket.

The reason for this is that the language functions of the cerebral cortex are localized to the left hemisphere in 95 percent of the population. Additionally, the left hemisphere is connected to the right side of the body through the corticospinal tract and the ascending tracts of the spinal cord. Motor commands from the precentral gyrus control the opposite side of the body, whereas sensory information processed by the postcentral gyrus is received from the opposite side of the body. For a verbal command to initiate movement of the right arm and hand, the left side of the brain needs to be connected by the corpus callosum. Language is processed in the left side of the brain and directly influences the left brain and right arm motor functions, but is sent to influence the right brain and left arm motor functions through the corpus callosum. Likewise, the left-handed sensory perception of what is in the left pocket travels across the corpus callosum from the right brain, so no verbal report on those contents would be possible if the hand happened to be in the pocket.

Watch the video titled The Man With Two Brains to see the neuroscientist Michael Gazzaniga introduce a patient he has worked with for years who has had his corpus callosum cut, separating his two cerebral hemispheres. A few tests are run to demonstrate how this manifests in tests of cerebral function. Unlike normal people, this patient can perform two independent tasks at the same time because the lines of communication between the right and left sides of his brain have been removed. Whereas a person with an intact corpus callosum cannot overcome the dominance of one hemisphere over the other, this patient can. If the left cerebral hemisphere is dominant in the majority of people, why would right-handedness be most common?

The cerebrum, particularly the cerebral cortex, is the location of important cognitive functions that are the focus of the mental status exam. The regionalization of the cortex, initially described on the basis of anatomical evidence of cytoarchitecture, reveals the distribution of functionally distinct areas. Cortical regions can be described as primary sensory or motor areas, association areas, or multimodal integration areas. The functions attributed to these regions include attention, memory, language, speech, sensation, judgment, and abstract reasoning.

The mental status exam addresses these cognitive abilities through a series of subtests designed to elicit particular behaviors ascribed to these functions. The loss of neurological function can illustrate the location of damage to the cerebrum. Memory functions are attributed to the temporal lobe, particularly the medial temporal lobe structures known as the hippocampus and amygdala, along with the adjacent cortex. Evidence of the importance of these structures comes from the side effects of a bilateral temporal lobectomy that were studied in detail in patient HM.

Losses of language and speech functions, known as aphasias, are associated with damage to the important integration areas in the left hemisphere known as Brocas or Wernickes areas, as well as the connections in the white matter between them. Different types of aphasia are named for the particular structures that are damaged. Assessment of the functions of the sensorium includes praxis and gnosis. The subtests related to these functions depend on multimodal integration, as well as language-dependent processing.

The prefrontal cortex contains structures important for planning, judgment, reasoning, and working memory. Damage to these areas can result in changes to personality, mood, and behavior. The famous case of Phineas Gage suggests a role for this cortex in personality, as does the outdated practice of prefrontal lobectomy.

Beneath the cerebral cortex are sets of nuclei known as subcortical nuclei that augment cortical processes. The nuclei of the basal forebrain serve as the primary location for acetylcholine production, which modulates the overall activity of the cortex, possibly leading to greater attention to sensory stimuli. Alzheimers disease is associated with a loss of neurons in the basal forebrain. The hippocampus and amygdala are medial-lobe structures that, along with the adjacent cortex, are involved in long-term memory formation and emotional responses. The basal nuclei are a set of nuclei in the cerebrum responsible for comparing cortical processing with the general state of activity in the nervous system to influence the likelihood of movement taking place. For example, while a student is sitting in a classroom listening to a lecture, the basal nuclei will keep the urge to jump up and scream from actually happening. (The basal nuclei are also referred to as the basal ganglia, although that is potentially confusing because the term ganglia is typically used for peripheral structures.)

The major structures of the basal nuclei that control movement are the caudate, putamen, and globus pallidus, which are located deep in the cerebrum. The caudate is a long nucleus that follows the basic C-shape of the cerebrum from the frontal lobe, through the parietal and occipital lobes, into the temporal lobe. The putamen is mostly deep in the anterior regions of the frontal and parietal lobes. Together, the caudate and putamen are called the striatum. The globus pallidus is a layered nucleus that lies just medial to the putamen; they are called the lenticular nuclei because they look like curved pieces fitting together like lenses. The globus pallidus has two subdivisions, the external and internal segments, which are lateral and medial, respectively. These nuclei are depicted in a frontal section of the brain in Figure 14.3.6.

The basal nuclei in the cerebrum are connected with a few more nuclei in the brain stem that together act as a functional group that forms a motor pathway. Two streams of information processing take place in the basal nuclei. All input to the basal nuclei is from the cortex into the striatum (Figure 14.3.7). The direct pathway is the projection of axons from the striatum to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr). The GPi/SNr then projects to the thalamus, which projects back to the cortex. The indirect pathway is the projection of axons from the striatum to the globus pallidus external segment (GPe), then to the subthalamic nucleus (STN), and finally to GPi/SNr. The two streams both target the GPi/SNr, but one has a direct projection and the other goes through a few intervening nuclei. The direct pathway causes the disinhibition of the thalamus (inhibition of one cell on a target cell that then inhibits the first cell), whereas the indirect pathway causes, or reinforces, the normal inhibition of the thalamus. The thalamus then can either excite the cortex (as a result of the direct pathway) or fail to excite the cortex (as a result of the indirect pathway).

The switch between the two pathways is the substantia nigra pars compacta, which projects to the striatum and releases the neurotransmitter dopamine. Dopamine receptors are either excitatory (D1-type receptors) or inhibitory (D2-type receptors). The direct pathway is activated by dopamine, and the indirect pathway is inhibited by dopamine. When the substantia nigra pars compacta is firing, it signals to the basal nuclei that the body is in an active state, and movement will be more likely. When the substantia nigra pars compacta is silent, the body is in a passive state, and movement is inhibited. To illustrate this situation, while a student is sitting listening to a lecture, the substantia nigra pars compacta would be silent and the student less likely to get up and walk around. Likewise, while the professor is lecturing, and walking around at the front of the classroom, the professors substantia nigra pars compacta would be active, in keeping with his or her activity level.

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the direct pathway is the shorter pathway through the system that results in increased activity in the cerebral cortex and increased motor activity. The direct pathway is described as resulting in disinhibition of the thalamus. What does disinhibition mean? What are the two neurons doing individually to cause this?

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the indirect pathway is the longer pathway through the system that results in decreased activity in the cerebral cortex, and therefore less motor activity. The indirect pathway has an extra couple of connections in it, including disinhibition of the subthalamic nucleus. What is the end result on the thalamus, and therefore on movement initiated by the cerebral cortex?

There is a persistent myth that people are right-brained or left-brained, which is an oversimplification of an important concept about the cerebral hemispheres. There is some lateralization of function, in which the left side of the brain is devoted to language function and the right side is devoted to spatial and nonverbal reasoning. Whereas these functions are predominantly associated with those sides of the brain, there is no monopoly by either side on these functions. Many pervasive functions, such as language, are distributed globally around the cerebrum.

Some of the support for this misconception has come from studies of split brains. A drastic way to deal with a rare and devastating neurological condition (intractable epilepsy) is to separate the two hemispheres of the brain. After sectioning the corpus callosum, a split-brained patient will have trouble producing verbal responses on the basis of sensory information processed on the right side of the cerebrum, leading to the idea that the left side is responsible for language function.

However, there are well-documented cases of language functions lost from damage to the right side of the brain. The deficits seen in damage to the left side of the brain are classified as aphasia, a loss of speech function; damage on the right side can affect the use of language. Right-side damage can result in a loss of ability to understand figurative aspects of speech, such as jokes, irony, or metaphors. Nonverbal aspects of speech can be affected by damage to the right side, such as facial expression or body language, and right-side damage can lead to a flat affect in speech, or a loss of emotional expression in speechsounding like a robot when talking. Damage to language areas on the right side causes a condition called aprosodia where the patient has difficulty understanding or expressing the figurative part of speech.

The diencephalon is the one region of the adult brain that retains its name from embryologic development. The etymology of the word diencephalon translates to through brain. It is the connection between the cerebrum and the rest of the nervous system, with one exception. The rest of the brain, the spinal cord, and the PNS all send information to the cerebrum through the diencephalon. Output from the cerebrum passes through the diencephalon. The single exception is the system associated with olfaction, or the sense of smell, which connects directly with the cerebrum. In the earliest vertebrate species, the cerebrum was not much more than olfactory bulbs that received peripheral information about the chemical environment (to call it smell in these organisms is imprecise because they lived in the ocean).

The diencephalon is deep beneath the cerebrum and constitutes the walls of the third ventricle. The diencephalon can be described as any region of the brain with thalamus in its name. The two major regions of the diencephalon are the thalamus itself and the hypothalamus (Figure 14.3.8). There are other structures, such as the epithalamus, which contains the pineal gland, or the subthalamus, which includes the subthalamic nucleus that is part of the basal nuclei.

The thalamus is a collection of nuclei that relay information between the cerebral cortex and the periphery, spinal cord, or brain stem. All sensory information, except for the sense of smell, passes through the thalamus before processing by the cortex. Axons from the peripheral sensory organs, or intermediate nuclei, synapse in the thalamus, and thalamic neurons project directly to the cerebrum. It is a requisite synapse in any sensory pathway, except for olfaction. The thalamus does not just pass the information on, it also processes that information. For example, the portion of the thalamus that receives visual information will influence what visual stimuli are important, or what receives attention.

The cerebrum also sends information down to the thalamus, which usually communicates motor commands. This involves interactions with the cerebellum and other nuclei in the brain stem. The cerebrum interacts with the basal nuclei, which involves connections with the thalamus. The primary output of the basal nuclei is to the thalamus, which relays that output to the cerebral cortex. The cortex also sends information to the thalamus that will then influence the effects of the basal nuclei.

Inferior and slightly anterior to the thalamus is the hypothalamus, the other major region of the diencephalon. The hypothalamus is a collection of nuclei that are largely involved in regulating homeostasis. The hypothalamus is the executive region in charge of the autonomic nervous system and the endocrine system through its regulation of the anterior pituitary gland. Other parts of the hypothalamus are involved in memory and emotion as part of the limbic system.

The midbrain and the pons and medulla of the hindbrainare collectively referred to as the brain stem (Figure 14.3.9). The structure emerges from the ventral surface of the forebrain as a tapering cone that connects the brain to the spinal cord. Attached to the brain stem, but considered a separate region of the adult brain, is the cerebellum. The midbrain coordinates sensory representations of the visual, auditory, and somatosensory perceptual spaces. The pons is the main connection with the cerebellum. The pons and the medulla regulate several crucial functions, including the cardiovascular and respiratory systems.

The cranial nerves connect through the brain stem and provide the brain with the sensory input and motor output associated with the head and neck, including most of the special senses. The major ascending and descending pathways between the spinal cord and brain, specifically the cerebrum, pass through the brain stem.

One of the original regions of the embryonic brain, the midbrain is a small region between the thalamus and pons. It is separated into the tectum and tegmentum, from the Latin words for roof and floor, respectively. The cerebral aqueduct passes through the center of the midbrain, such that these regions are the roof and floor of that canal.

The tectum is composed of four bumps known as the colliculi (singular = colliculus), which means little hill in Latin. The inferior colliculus is the inferior pair of these enlargements and is part of the auditory brain stem pathway. Neurons of the inferior colliculus project to the thalamus, which then sends auditory information to the cerebrum for the conscious perception of sound. The superior colliculus is the superior pair and combines sensory information about visual space, auditory space, and somatosensory space. Activity in the superior colliculus is related to orienting the eyes to a sound or touch stimulus. If you are walking along the sidewalk on campus and you hear chirping, the superior colliculus coordinates that information with your awareness of the visual location of the tree right above you. That is the correlation of auditory and visual maps. If you suddenly feel something wet fall on your head, your superior colliculus integrates that with the auditory and visual maps and you know that the chirping bird just relieved itself on you. You want to look up to see the culprit, but do not.

The tegmentum is continuous with the gray matter of the rest of the brain stem. Throughout the midbrain, pons, and medulla, the tegmentum contains the nuclei that receive and send information through the cranial nerves, as well as regions that regulate important functions such as those of the cardiovascular and respiratory systems.

The word pons comes from the Latin word for bridge. It is visible on the anterior surface of the brain stem as the thick bundle of white matter attached to the cerebellum. The pons is the main connection between the cerebellum and the brain stem. The bridge-like white matter is only the anterior surface of the pons; the gray matter beneath that is a continuation of the tegmentum from the midbrain. Gray matter in the tegmentum region of the pons contains neurons receiving descending input from the forebrain that is sent to the cerebellum.

The medulla is the region known as the myelencephalon in the embryonic brain. The initial portion of the name, myel, refers to the significant white matter found in this regionespecially on its exterior, which is continuous with the white matter of the spinal cord. The tegmentum of the midbrain and pons continues into the medulla because this gray matter is responsible for processing cranial nerve information. A diffuse region of gray matter throughout the brain stem, known as the reticular formation, is related to sleep and wakefulness, such as general brain activity and attention.

The cerebellum, as the name suggests, is the little brain. It is covered in gyri and sulci like the cerebrum, and looks like a miniature version of that part of the brain (Figure 14.3.10). The cerebellum is largely responsible for comparing information from the cerebrum with sensory feedback from the periphery through the spinal cord. It accounts for approximately 10 percent of the mass of the brain.

Descending fibers from the cerebrum have branches that connect to neurons in the pons. Those neurons project into the cerebellum, providing a copy of motor commands sent to the spinal cord. Sensory information from the periphery, which enters through spinal or cranial nerves, is copied to a nucleus in the medulla known as the inferior olive. Fibers from this nucleus enter the cerebellum and are compared with the descending commands from the cerebrum. If the primary motor cortex of the frontal lobe sends a command down to the spinal cord to initiate walking, a copy of that instruction is sent to the cerebellum. Sensory feedback from the muscles and joints, proprioceptive information about the movements of walking, and sensations of balance are sent to the cerebellum through the inferior olive and the cerebellum compares them. If walking is not coordinated, perhaps because the ground is uneven or a strong wind is blowing, then the cerebellum sends out a corrective command to compensate for the difference between the original cortical command and the sensory feedback. The output of the cerebellum is into the midbrain, which then sends a descending input to the spinal cord to correct the messages going to skeletal muscles.

The description of the CNS is concentrated on the structures of the brain, but the spinal cord is another major organ of the system. Whereas the brain develops out of expansions of the neural tube into primary and then secondary vesicles, the spinal cord maintains the tube structure and is only specialized into certain regions. As the spinal cord continues to develop in the newborn, anatomical features mark its surface. The anterior midline is marked by the anterior median fissure, and the posterior midline is marked by the posterior median sulcus. Axons enter the posterior side through the dorsal (posterior) nerve root, which marks the posterolateral sulcus on either side. The axons emerging from the anterior side do so through the ventral (anterior) nerve root. Note that it is common to see the terms dorsal (dorsal = back) and ventral (ventral = belly) used interchangeably with posterior and anterior, particularly in reference to nerves and the structures of the spinal cord. You should learn to be comfortable with both.

On the whole, the posterior regions are responsible for sensory functions and the anterior regions are associated with motor functions. This comes from the initial development of the spinal cord, which is divided into the basal plate and the alar plate. The basal plate is closest to the ventral midline of the neural tube, which will become the anterior face of the spinal cord and gives rise to motor neurons. The alar plate is on the dorsal side of the neural tube and gives rise to neurons that will receive sensory input from the periphery.

The length of the spinal cord is divided into regions that correspond to the regions of the vertebral column. The name of a spinal cord region corresponds to the level at which spinal nerves pass through the intervertebral foramina. Immediately adjacent to the brain stem is the cervical region, followed by the thoracic, then the lumbar, and finally the sacral region. The spinal cord is not the full length of the vertebral column because the spinal cord does not grow significantly longer after the first or second year, but the skeleton continues to grow. The nerves that emerge from the spinal cord pass through the intervertebral formina at the respective levels. As the vertebral column grows, these nerves grow with it and result in a long bundle of nerves that resembles a horses tail and is named the cauda equina. The sacral spinal cord is at the level of the upper lumbar vertebral bones. The spinal nerves extend from their various levels to the proper level of the vertebral column.

In cross-section, the gray matter of the spinal cord has the appearance of an ink-blot test, with the spread of the gray matter on one side replicated on the othera shape reminiscent of a bulbous capital H. As shown in Figure 14.3.11, the gray matter is subdivided into regions that are referred to as horns. The posterior horn is responsible for sensory processing. The anterior horn sends out motor signals to the skeletal muscles. The lateral horn, which is only found in the thoracic, upper lumbar, and sacral regions, is the central component of the sympathetic division of the autonomic nervous system.

Some of the largest neurons of the spinal cord are the multipolar motor neurons in the anterior horn. The fibers that cause contraction of skeletal muscles are the axons of these neurons. The motor neuron that causes contraction of the big toe, for example, is located in the sacral spinal cord. The axon that has to reach all the way to the belly of that muscle may be a meter in length. The neuronal cell body that maintains that long fiber must be quite large, possibly several hundred micrometers in diameter, making it one of the largest cells in the body.

Just as the gray matter is separated into horns, the white matter of the spinal cord is separated into columns. Ascending tracts of nervous system fibers in these columns carry sensory information up to the brain, whereas descending tracts carry motor commands from the brain. Looking at the spinal cord longitudinally, the columns extend along its length as continuous bands of white matter. Between the two posterior horns of gray matter are the posterior columns. Between the two anterior horns, and bounded by the axons of motor neurons emerging from that gray matter area, are the anterior columns. The white matter on either side of the spinal cord, between the posterior horn and the axons of the anterior horn neurons, are the lateral columns. The posterior columns are composed of axons of ascending tracts. The anterior and lateral columns are composed of many different groups of axons of both ascending and descending tractsthe latter carrying motor commands down from the brain to the spinal cord to control output to the periphery.

Watch this video to learn about the gray matter of the spinal cord that receives input from fibers of the dorsal (posterior) root and sends information out through the fibers of the ventral (anterior) root. As discussed in this video, these connections represent the interactions of the CNS with peripheral structures for both sensory and motor functions. The cervical and lumbar spinal cords have enlargements as a result of larger populations of neurons. What are these enlargements responsible for?

Parkinsons disease is neurodegenerative, meaning that neurons die that cannot be replaced, so there is no cure for the disorder. Treatments for Parkinsons disease are aimed at increasing dopamine levels in the striatum. Currently, the most common way of doing that is by providing the amino acid L-DOPA, which is a precursor to the neurotransmitter dopamine and can cross the blood-brain barrier. With levels of the precursor elevated, the remaining cells of the substantia nigra pars compacta can make more neurotransmitter and have a greater effect. Unfortunately, the patient will become less responsive to L-DOPA treatment as time progresses, and it can cause increased dopamine levels elsewhere in the brain, which are associated with psychosis or schizophrenia.

Visit this site for a thorough explanation of Parkinsons disease.

Compared with the nearest evolutionary relative, the chimpanzee, the human has a brain that is huge. At a point in the past, a common ancestor gave rise to the two species of humans and chimpanzees. That evolutionary history is long and is still an area of intense study. But something happened to increase the size of the human brain relative to the chimpanzee. Read this article in which the author explores the current understanding of why this happened.

According to one hypothesis about the expansion of brain size, what tissue might have been sacrificed so energy was available to grow our larger brain? Based on what you know about that tissue and nervous tissue, why would there be a trade-off between them in terms of energy use?

Have you ever heard the claim that humans only use 10 percent of their brains? Maybe you have seen an advertisement on a website saying that there is a secret to unlocking the full potential of your mindas if there were 90 percent of your brain sitting idle, just waiting for you to use it. If you see an ad like that, dont click. It isnt true.

An easy way to see how much of the brain a person uses is to take measurements of brain activity while performing a task. An example of this kind of measurement is functional magnetic resonance imaging (fMRI), which generates a map of the most active areas and can be generated and presented in three dimensions (Figure 14.3.12). This procedure is different from the standard MRI technique because it is measuring changes in the tissue in time with an experimental condition or event.

The underlying assumption is that active nervous tissue will have greater blood flow. By having the subject perform a visual task, activity all over the brain can be measured. Consider this possible experiment: the subject is told to look at a screen with a black dot in the middle (a fixation point). A photograph of a face is projected on the screen away from the center. The subject has to look at the photograph and decipher what it is. The subject has been instructed to push a button if the photograph is of someone they recognize. The photograph might be of a celebrity, so the subject would press the button, or it might be of a random person unknown to the subject, so the subject would not press the button.

In this task, visual sensory areas would be active, integrating areas would be active, motor areas responsible for moving the eyes would be active, and motor areas for pressing the button with a finger would be active. Those areas are distributed all around the brain and the fMRI images would show activity in more than just 10 percent of the brain (some evidence suggests that about 80 percent of the brain is using energybased on blood flow to the tissueduring well-defined tasks similar to the one suggested above). This task does not even include all of the functions the brain performs. There is no language response, the body is mostly lying still in the MRI machine, and it does not consider the autonomic functions that would be ongoing in the background.

Considering the anatomical regions of the nervous system, there are specific names for the structures within each division. A localized collection of neuron cell bodies is referred to as a nucleus in the CNS and as a ganglion in the PNS. A bundle of axons is referred to as a tract in the CNS and as a nerve in the PNS. Whereas nuclei and ganglia are specifically in the central or peripheral divisions, axons can cross the boundary between the two. A single axon can be part of a nerve and a tract. The name for that specific structure depends on its location.

Nervous tissue can also be described as gray matter and white matter on the basis of its appearance in unstained tissue. These descriptions are more often used in the CNS. Gray matter is where nuclei are found and white matter is where tracts are found. In the PNS, ganglia are basically gray matter and nerves are white matter.

The adult brain is separated into four major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum. The cerebrum is the largest portion and contains the cerebral cortex and subcortical nuclei. It is divided into two halves by the longitudinal fissure.

The cortex is separated into the frontal, parietal, temporal, and occipital lobes. The frontal lobe is responsible for motor functions, from planning movements through executing commands to be sent to the spinal cord and periphery. The most anterior portion of the frontal lobe is the prefrontal cortex, which is associated with aspects of personality through its influence on motor responses in decision-making.

The other lobes are responsible for sensory functions. The parietal lobe is where somatosensation is processed. The occipital lobe is where visual processing begins, although the other parts of the brain can contribute to visual function. The temporal lobe contains the cortical area for auditory processing, but also has regions crucial for memory formation.

Nuclei beneath the cerebral cortex, known as the subcortical nuclei, are responsible for augmenting cortical functions. The basal nuclei receive input from cortical areas and compare it with the general state of the individual through the activity of a dopamine-releasing nucleus. The output influences the activity of part of the thalamus that can then increase or decrease cortical activity that often results in changes to motor commands. The basal forebrain is responsible for modulating cortical activity in attention and memory. The limbic system includes deep cerebral nuclei that are responsible for emotion and memory.

The diencephalon includes the thalamus and the hypothalamus, along with some other structures. The thalamus is a relay between the cerebrum and the rest of the nervous system. The hypothalamus coordinates homeostatic functions through the autonomic and endocrine systems.

The brain stem is composed of the midbrain, pons, and medulla. It controls the head and neck region of the body through the cranial nerves. There are control centers in the brain stem that regulate the cardiovascular and respiratory systems.

The cerebellum is connected to the brain stem, primarily at the pons, where it receives a copy of the descending input from the cerebrum to the spinal cord. It can compare this with sensory feedback input through the medulla and send output through the midbrain that can correct motor commands for coordination.

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the direct pathway is the shorter pathway through the system that results in increased activity in the cerebral cortex and increased motor activity. The direct pathway is described as resulting in disinhibition of the thalamus. What does disinhibition mean? What are the two neurons doing individually to cause this?

Both cells are inhibitory. The first cell inhibits the second one. Therefore, the second cell can no longer inhibit its target. This is disinhibition of that target across two synapses.

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the indirect pathway is the longer pathway through the system that results in decreased activity in the cerebral cortex, and therefore less motor activity. The indirect pathway has an extra couple of connections in it, including disinhibition of the subthalamic nucleus. What is the end result on the thalamus, and therefore on movement initiated by the cerebral cortex?

By disinhibiting the subthalamic nucleus, the indirect pathway increases excitation of the globus pallidus internal segment. That, in turn, inhibits the thalamus, which is the opposite effect of the direct pathway that disinhibits the thalamus.

Watch this video to learn about the gray matter of the spinal cord that receives input from fibers of the dorsal (posterior) root and sends information out through the fibers of the ventral (anterior) root. As discussed in this video, these connections represent the interactions of the CNS with peripheral structures for both sensory and motor functions. The cervical and lumbar spinal cords have enlargements as a result of larger populations of neurons. What are these enlargements responsible for?

There are more motor neurons in the anterior horns that are responsible for movement in the limbs. The cervical enlargement is for the arms, and the lumbar enlargement is for the legs.

Compared with the nearest evolutionary relative, the chimpanzee, the human has a brain that is huge. At a point in the past, a common ancestor gave rise to the two species of humans and chimpanzees. That evolutionary history is long and is still an area of intense study. But something happened to increase the size of the human brain relative to the chimpanzee. Read this article in which the author explores the current understanding of why this happened.

According to one hypothesis about the expansion of brain size, what tissue might have been sacrificed so energy was available to grow our larger brain? Based on what you know about that tissue and nervous tissue, why would there be a trade-off between them in terms of energy use?

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14.3 The Brain and Spinal Cord Anatomy & Physiology

VANCOUVER, Washington, Dec. 23, 2022 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTCQB: CYDY) ("CytoDyn" or the "Company"), a biotechnology company developing leronlimab, a CCR5 antagonist with the potential for multiple therapeutic indications, will hold a webcast on December 29, 2022 at 8:00 a.m. Pacific Time (11:00 a.m. Eastern Time) to discuss the performance of leronlimab in its clinical trials and the recent charges against its former CEO Nader Pourhassan, who was previously terminated on January 24, 2022, and has had no affiliation with the Company since that time.

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CytoDyn to Hold Webcast to Discuss the Performance of Leronlimab in Clinical Trials and Recent Charges Against Former CEO

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An organoid model of colorectal circulating tumor cells with stem cell ...

HAMILTON, Bermuda, Nov. 30, 2022 (GLOBE NEWSWIRE) -- Kiniksa Pharmaceuticals, Ltd. (Nasdaq: KNSA) announced today that management will participate in a fireside chat at the Bank of America Securities 2022 Biotech SMID Cap Conference on Wednesday, December 7, 2022 at 10:15 a.m. Eastern Time.

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Kiniksa Pharmaceuticals to Present at Bank of America Securities 2022 Biotech SMID Cap Conference

LOS ANGELES, Nov. 30, 2022 (GLOBE NEWSWIRE) -- (NASDAQ: ENOB) -- On November 23, 2022, Enochian BioSciences Inc. (the "Company") received a notice (the "Notice") from The Nasdaq Stock Market LLC ("Nasdaq") stating that because the Company has not yet filed its Form 10-Q for the period ended September 30, 2022 (the “Form 10-Q”), the Company remains in non-compliance with Nasdaq Listing Rule 5250(c)(1), which requires listed companies to timely file all required periodic financial reports with the Securities and Exchange Commission (the "SEC"). As previously disclosed on Form 8-K filed with the Securities and Exchange Commission on October 21, 2022, on October 17, 2022, the Company previously received a notice from Nasdaq indicating that as a result of not having timely filed its Annual Report on Form 10-K for the period ended June 30, 2022 (the "Form 10-K"), the Company was not in compliance with Nasdaq Listing Rule 5250(c)(1).

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Burn wound healing involves a series of complex processes which are subject to intensive investigations to improve the outcomes, in particular, the healing time and the quality of the scar. Burn injuries, especially severe ones, are proving to have devastating effects on the affected patients. Stem cells have been recently applied in the field to promote superior healing of the wounds. Not only have stem cells been shown to promote better and faster healing of the burn wounds, but also they have decreased the inflammation levels with less scar progression and fibrosis. This review aims to highlight the beneficial therapeutic effect of stem cells in burn wound healing and to discuss the involved pathways and signaling molecules. The review covers various types of burn wound healing like skin and corneal burns, along with the alternative recent therapies being studied in the field of burn wound healing. The current reflection of the attitudes of people regarding the use of stem cells in burn wound healing is also stated.

The use of stem cell therapy is the yet to be discovered gold mine of science. A myriad of studies using stem cells are being done with promising results in various fields ranging from oncologic and hematologic diseases to organ transplants and wound healing. In the field of wound healing, the use of different types of stem cells has been reported for different types of wounds [13]. Burn wounds were of special interest due to the large number of cases of burns encountered nowadays, especially in the Middle Eastern Region and specifically in those areas with armed conflicts. Burn wounds have proven to be capable of having a devastating effect both functionally and cosmetically, necessitating the search for a better and more efficient cure. Being a very hot topic in the present field of research with constant studies and updates necessitated an updated review that encompasses the recent advances in stem cell therapy for burn wound healing in addition to relevant experimental studies. The literature was searched using the key words burn, stem cells, and wound healing. CINAHL, PubMed, EMBASE, and Medline were used as search engines to broaden the resources. The studies reported were not limited neither to humans nor by language and were mostly on animals unless otherwise specified. They are mostly reported in a chronological order of their publication dates, except when found relevant to group and mentioning some related studies consecutively.

Stem cells are undifferentiated pluripotential cells that are capable of producing other types of cells, including new stem cells identical to mother cells [4]. Stem cells can be of embryonal origin or adult origin, depending on the type of tissue they are derived from [4]. Embryonal stem cells are derived from either embryonal tissue or from germ cells in adults [4]. On the other hand, adult stem cells are derived from adult tissues of different organs, especially those with a high turnover rate such as intestines and bone marrow [4].

Stem cells have been implicated in the healing of wounds in general. However, the methods of application of the stem cells in burn wound healing are diverse, including topical application, local injection, intravenous or systemic injection, and dermal or carrier application. Several studies have shown the efficacy of stem cells in promoting faster and superior wound healing. Alexaki et al. [5] successfully used adipose derived mesenchymal stem cells in wound healing in mice and compared their effect with dermal fibroblasts. The application of stem cells in wounds promoted more efficient reepithelialization by their proliferative effect on keratinocytes [5]. Moreover, this effect of stem cells was found to be mediated by keratinocyte growth factor-1 (KGF-1) and platelet derived growth factor-BB (PDGF-BB) [5]. Amniotic fluid derived stem cells have also been used in wound healing. Skardal et al. [6] tested the effect of amniotic fluid derived stem cells in wound healing in a mouse model. Wound closure, reepithelialization, and angiogenesis were more rapid in mice treated with the stem cells in comparison to those treated with fibrin collagen gel only [6]. Additionally, stem cells did not integrate permanently in the tissue, thus, suggesting that their effect is due to released factors and not by direct interaction [6]. Additionally, bone marrow derived mesenchymal stem cells have also been used in wound healing. Leonardi et al. [7] utilized bone marrow derived stem cells in artificial dermal substitutes to promote wound healing. These stem cells were shown to increase vascular density in the wounds along with the rate of reepithelialization [7]. A study by Zhang et al. [8] examined the effect of activin signaling on the homing of stem cells to wound sites. It was also found that JNK and ERK signaling pathways were involved in activin signaling and eventually the homing of stem cells [8].

Concerning the physiology by which stem cells enhance the process of burn wound healing, several studies have been reported. Mansilla et al. [9] found evidence of cells in the bloodstream with identical phenotypes to mesenchymal bone marrow stem cells after acute large skin burns. Hence, it was concluded that these stem cells may have a role in promoting wound healing in burns. In a similar study, Fox et al. [10] reported increased levels of bone marrow derived endothelial progenitor cells in burn patients. These levels were proportional to the extent of the burn. The study also showed increased levels of angiogenic cytokines which may be involved in the signaling pathway for promoting the release of bone marrow derived stem cells. Focusing on the role of cytokines in burn wound healing, Payne et al. [11] studied the role of amnion derived cellular cytokine solution. In the study, Payne et al. used amnion derived multipotent progenitor cells to harvest cytokines and apply them in burn wound healing. Amnion derived cellular cytokine solution showed statistically significant improvement in the epithelialization of the burn wounds and the appearance of hair growth compared to controls [11]. In addition, the results demonstrated a faster epithelialization in burn wounds with increased frequency of application of the cytokines, further strengthening the role of stem cell derived cytokines in burn wound healing [11]. Furthermore, Foresta et al. [12] reported a positive linear correlation between endothelial progenitor cell blood levels and the total body surface area burnt. There was an increased level of endothelial progenitor cells in the bloodstream after escharectomy, posing a possible role of escharectomy in burn wound healing [12]. Additionally, stem cells could work by the release of bioactive peptides as proposed by Cabrera et al. [13] in their study where they showed that stem cells have an active role in burn wound healing by producing bioactive peptides, such as thymosin 4 and others.

More recent studies have also highlighted the role of stem cells in the process of wound healing in general and burn wound healing in specific. Koenen et al. [14] isolated acute wound fluids and chronic wound fluids and compared their effects on adipose tissue derived stem cell function in wounds. They came to the conclusion that acute wound fluids had a positive effect on the proliferation of adipose derived stem cells in wounds [14] while chronic wound fluids had a negative effect; the mentioned findings might explain the insufficient and slow healing process in chronic wounds due to a stem cell deficiency [14]. Furthermore, stem cells have been shown to decrease dermal fibrosis development in burn wound healing in mice [15]. Wu et al. performed a series of experiments which showed that bone marrow derived mesenchymal stem cells stimulate the formation of a basket weave organization of collagen in bleomycin treated skin, similar to normal skin [15]. Additionally, stem cell treatment of the skin decreased markers of myofibroblasts and downregulated type I collagen, leading to a decrease in the fibrosis that could have occurred to the skin [15]. Consequently, the role of stem cells in decreasing bleomycin induced fibrosis may be extrapolated to decrease fibrosis in burn wounds and improve their healing with less scar formation. Moreover, Lough et al. [16] performed a study in mice which showed a role for intestine derived human alpha defensin 5 in enhancing wound healing and decreasing its bacterial load. It induces leucine-rich repeat-containing G-protein-coupled receptors which are markers of adult epithelial stem cells both in skin and intestine [16]. Also implicated in the role of stem cells in burn wound healing is the role of SDF-1/CXCR4 signaling; Ding et al. [17] used interferon a2b in patients with burn wounds to suppress SDF-1/CXCR4 signaling. They found out that the decreased levels of signaling lead to better remodeling of hypertrophic scarring in the wounds [17]. Additional studies on the CXCR4 signaling pathway were done by Yang et al. [18] on irradiated mice. The mice having an overexpression of CXCR4, a receptor involved in the homing and migration of several stem cell types, showed an accelerated wound healing time [18]. Furthermore, Hu et al. [19] injected bone marrow derived mesenchymal stem cells into mice and studied the effect of blocking CXCR4 receptors. They found out that blocking the CXCL12/CXCR4 pathway, leading to activation of CXCR4, caused delayed wound closure in inflicted burn wounds. Moreover, CXCL12 levels were elevated in the burn wound one week after injury [19]. Hence, stem cells seem to be attracted to and attach to the burnt injury site by the CXCL12/CXCR4 pathway involving the CXCR4 receptors [18, 19]. The role of the ligand for the CXCR4 receptors, stromal cell derived factor-1 alpha (SDF-1a), has also been studied. L et al. [20] performed a study on the role of SDF-1a and its relation to the expression of miR-27b. It was found that SDF-1a expression was suppressed by direct binding of the miRNA to its 39UTR site [20]. As expected, miRNA expression was suppressed in wounds hence allowing better SDF-1a signaling and more homing of stem cells to the burn wounds [20]. In particular, miR-27b was found to be involved in the burn margins of wounds and in the mobilization of stem cells to the epidermis [20]. Chen et al. [21] performed experiments using porcine acellular dermal matrix on rats with inflicted 2nd degree burns. It stimulated collagen synthesis and stem cell proliferation and differentiation; porcine acellular matrix treated rats had a better and faster healing of the wounds.

Thus, in brief, the process of burn wound healing involves different types of growth factors, receptors, and cytokines. These factors are related to stem cell homing, differentiation, and proliferation. Additionally, when applied to burn wounds, they led to a better and faster healing process.

The use of stem cells for burn wound healing, as reported in the literature, dates back to 2003 with Shumakov et al. [22]. Shumakov et al. were the first to use mesenchymal bone marrow derived stem cells (BMSC) in burn wound healing and compared them to embryonic fibroblasts [22]. The experiments were done on rats where mesenchymal bone marrow derived stem cells were applied to wounds showing decreased cell infiltration of the wound and an accelerated formation of new vessels and granulation tissue in comparison with embryonic fibroblasts and controls (burn wounds with no transplanted cells) [22]. Hence, this study marked a new era in the research of burn wound healing by being the first to test the use of stem cells in this complex process. Following this, a study by Chunmeng et al. [23] found that systemic transplantation of dermis derived multipotent cells promoted the healing of wounds in irradiated rats compared to controls with no transplantation, noting that topical transplantation of the cells had no superior effect. In 2004, Rasulov et al. [24] were the first to report using bone marrow mesenchymal stem cells in humans; a female patient with extensive skin burns (IIIB 30% of body surface area) had the stem cells applied onto the burn surface. The application of stem cells caused faster wound healing and active neoangiogenesis [24]. Another study done by Rasulov et al. on rats also showed the superiority of stem cells in burn wound healing [25]. In the rat study, the application of mesenchymal stem cells on burns reduced cell infiltration, improved neoangeogenesis, and reduced the formation of granulation tissue [25]. The aforementioned conditions created a better medium for wound healing in burns. In a similar effort, Liu et al. [26] performed experiments on pigs where they applied collagen scaffolds with seeded mesenchymal stem cells onto the surface of inflicted burns; the latter were found to induce better burn wound healing with less contraction and better vascularization and keratinization. Moreover, in human cutaneous radiation wounds, Lataillade et al. [27, 28] reported two cases where stem cells where used to aid in burn wound healing. Mesenchymal stem cells were applied, in addition to surgical excision, flaps, and grafts, to burn wounds of cutaneous radiation patients. In these patients, the application of the mesenchymal stem cells decreased the levels of inflammation and promoted a better healing [27, 28]. Further on the role of stem cells in irradiated skin were the studies conducted by Dong et al. [29, 30], where they additionally inserted a vector of human beta defensin 2 into the stem cells. The mentioned studies showed a positive role for stem cells transfected with beta defensin 2 in burn wound healing by exhibiting antibacterial properties in infected burn wounds [29, 30]. In a similar experiment, Ha et al. [31] transfected mesenchymal stem cells with vectors of hepatocyte growth factor. The experiment, done on rats, compared the wound healing of a partial thickness burn treated with stem cells alone or stem cells transfected with hepatocyte growth factor [31]. The group treated with the transfected stem cells showed a significantly larger range of reepidermalization starting the first week, along with a thicker epidermis and lower content of collagen I at 3 weeks after burn [31]. In the same year (2010), Agay et al. [32] performed experimental studies by inflicting pigs with cutaneous radiation and studying the role of stem cells in the healing of the wounds. Intradermal mesenchymal stem cell injections were given locally in the affected area. They led to the accumulation of lymphocytes in the wound with better vascularization compared to controls (pigs with no injections of mesenchymal stem cells) [32]. Later on, Riccobono et al. [33] studied, in another experiment, the role of adipose tissue derived stem cells in the treatment of cutaneous radiation. Autologous, allogeneic, and acellular (empty, control) vehicles of adipose derived stem cells were grafted onto the burn wound areas [33]. Autologous but not allogeneic adipose derived stem cells were found to promote superior burn wound healing with no necrosis and decreased pain [33].

Aside to direct stem cell application to burn wounds, Kinoshita et al. [34] inflicted cutaneous radiation wounds to pigs and used expanders with and without basic fibroblast growth factor to determine their effect on burn wound healing. The group with basic fibroblast growth factor and expander showed greater proliferation of the dermis and epidermis along with increased neoangiogenesis [34]. Thus, basic fibroblast growth factor, which is known to promote the proliferation of mesenchymal stem cells, improved burn wound healing [34, 35].

In 2010, Yan et al. [36] studied the efficacy of porcine bone marrow derived mesenchymal stem cells combined with skin derived keratinocytes, both infected with recombinant retrovirus expressing human (h) platelet derived growth factor-A, in the healing of irradiated skin. The cells were loaded onto a cultured cutaneous substitute and compared their effect on healing with a cell-free cultured cutaneous substitute [36]. The substitute with cells stimulated faster healing, epithelialization, angiogenesis, and better granulation of the burn wound [36]. In another experiment, Collawn et al. [37] inflicted laser burn wounds to organotypic raft cultures. The burn wounds were treated with dermal grafts with and without adipose derived stromal cells [37]. The adipose derived stromal cell-containing grafts showed complete healing of the epidermis after two days, whereas the cell-free grafts still had areas of injury; hence, those stem cells had a role in promoting faster healing of the burnt areas [37]. More on cutaneous radiation treatment came from Xia et al. [38] who transfected human vascular endothelial growth factor 165 and human beta defensin 3 into bone marrow derived mesenchymal stem cells and used the cells to treat irradiated skin. The stem cell treated area, in comparison with cell-free controls, showed shorter healing times with better granulation and collagen deposition [38]. Additionally, Xue et al. [39] examined the effect of human mesenchymal stem cells in mouse models. Mice with inflicted burn wounds were injected locally, in the burn area, with the stem cells (controls injected cell-free injections) [39]. Wound healing was significantly faster when stem cells were included in the injection with an increased and denser neoangiogenesis [39]. Stem cell injections also had a role in resuming activity and regaining body weight more rapidly [39]. Similarly, Mansilla et al. [40] used mesenchymal stem cells in burn wound healing in pigs through an acellular dermal matrix embedded with anti-CD44 antibodies to promote homing and attachment of the stem cells [40]. This study concluded that the use of these dermal matrices with stem cells not only promoted better healing of the burn wound, but also stimulated the formation of hair follicles and regeneration of muscles and ribs [40].

Concerning stem cells from human umbilical cords, Liu et al. [41] studied the effect of human umbilical cord derived mesenchymal stem cells in the healing of severe burns inflicted in rats. The stem cells were intravenously injected into the affected rats [41]. Liu et al. found that the injection of the stem cells into the rats accelerated the wound healing compared to controls, decreased the count of inflammatory cells, downregulated interleukins 1 and 6, and increased the levels of interleukin 10 and TSG-6 [41]. Moreover, stem cell injected rats had increased neovascularization and VEGF levels [41]. Not only do stem cells promote faster wound healing in burns, but also they prevent the progression of burn injuries as showed by Singer et al. [42]. The latter performed an experiment while inflicting thermal burns to rats, with several rectangular burns on each rat separated by unburned interspaces [42]. Some of the rats received tail vein injections of mesenchymal stem cells, while others received saline injections [42]. After 7 days, all of the unburned spaces in the controls were necrotic [42]. However, 20% of the unburned spaces in rats with stem cells injections did not necrose [42]. Consequently, stem cells were also shown to play a possible role in the prevention of progression of burn injuries. Furthermore, in a study by Xu et al. [43], applying autologous bone marrow derived mesenchymal stem cells to grafted burn wounds, they demonstrated decreased contraction of the grafts.

In 2014, Yang et al. [44] attempted to integrate mesenchymal stem cells with fibrin glue into the dressing of burn wounds. They inflicted scald wounds on the back of rats and applied dressing with fibrin glue and stem cells in one group, fibrin glue only in the second, and no intervention in the third [44]. One month later, the treatment group with fibrin glue and stem cells showed significantly faster healing than the other two; moreover, this group had more proliferation of sebaceous glands and the appearance of hair follicle-like structures which were not present in the other groups [44]. In another experiment, Lough et al. [45] isolated leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6+) epithelial stem cells from the adnexal compartment of the skin of mice. They injected the harvested stem cells locally into inflicted burn wounds [45]. The wounds injected with stem cells showed a better healing along with increased vascular endothelial growth factor, platelet derived growth factor, and epidermal growth factor levels [45]. Stem cell injection also promoted the formation of nascent hair follicles and better neoangiogenesis in the wounds of the affected mice [45].

On the other hand, it is very pertinent to report another study in 2014 by Loder et al. [46] where they also tested the effect of adipose derived stem cells in the treatment of burns. The mice with inflicted burns that received stem cells injections showed no significant difference in comparison to controls (received saline injections) with respect to proliferation and vascularization [46]. Nevertheless, the role of stem cells in burn wound healing is a dynamic field and still under extensive research.

Another area of particular interest in the field of burn wound healing is the chemical burns of the cornea. In the year 2000, Dua and Azuara-Blanco [47] used autologous limbal stem cells for ocular surface reconstruction of the contralateral eye. It resulted in the formation of a better corneal surface with significant improvement in the vision and symptoms of the patients [47]. Several other experiments and trials using limbal stem cells showed similar results in inducing improvement of corneal healing and decreased neovascularization in both human (adults and children) and animal subjects [4853]. In 2007, Oh et al. [54] studied the therapeutic effects of mesenchymal stem cells on corneas with chemical burns. They reported that mesenchymal stem cell media and mesenchymal stem cell culture media (without the stem cells) reduced the inflammation and promoted neovascularization of the corneas [54]. They were also found to reduce the infiltration of CD4 cells, as well as IL-6, IL-10, and TGF-B1 levels. It is to be noted that the direct application of the stem cells provided superior results in the healing process in comparison with the stem cell culture media [54]. Another study by Ye et al. [55] utilized cyclophosphamide to suppress inflammatory reactions and the release of bone marrow stem cells into circulation. In this study, rabbits were inflicted with corneal alkali injuries. It was found that rabbits with an unsuppressed bone marrow had significantly greater reepithelialization of the corneas with clearer surfaces [55]. Thus, this study revealed the role of bone marrow cells in enhancing the healing of corneal chemical wounds. Furthermore, Sel et al. [56] inflicted alkali wounds on the corneal surfaces of mice and treated the corneas with bone marrow derived stem cells, CD117+ cells, or medium only as control. Reepithelialization of the wounds in the treatment groups was significantly faster than the control, with no difference in corneal transparency. Stem cells and CD117+ cells were absent from corneas after healing, thus suggesting that soluble factors may be responsible for the effect of the applied cells [56]. In a different study by Rama et al. [57], limbal stem cells were cultured on fibrin and used in corneal burns; not only did stem cells promote a better healing but also they had maintained a superior healing at a follow-up of 10 years later. Several other studies showed comparable results where mesenchymal derived or adipose derived stem cells promoted faster recovery of the corneal epithelium and decreased neovascularization, inflammation, and oxidative injury; moreover, stem cells stimulated the formation of clearer cornea media in some experiments [5861]. Additionally, Basu et al. [6264], in 2011 and 2012, reported a series of studies concerning the use of limbal stem cells in corneal burn wound healing. In the first study, Basu et al. [62] used limbal stem cells in corneal burn wound healing and followed them by penetrating keratoplasty procedures. Good results were observed but they were not compared to controls. However, in the second study, Basu et al. [63] observed that 66% of patients who failed primary procedures of corneal repair and who were subjected to a secondary limbal stem cell transplant on the affected cornea had successful improvement of the corneal surface with no neovascularization at a follow-up of two years. Later on, Sangwan et al. [64] used limbal biopsies from unaffected eyes and cultured them on amniotic membranes as substrates. Similar results to previous experiments were obtained with avascular epithelialization of the new corneal surfaces [64]. Furthermore and as demonstrated by Huang et al. [65], the use of allograft transplants of limbal stem cells in corneal burn wound healing also resulted in improved avascular corneal healing without the need for systemic immunosuppression. Pellegrini et al. [66] studied the biological factors that affected the stem cells role in corneal burn wound healing; the accurate number of stem cells used expressing high levels of the p63 transcription factor was shown to have important influence.

Stem cells do seem to have a very promising role in the treatment of burn wounds; however, other therapies are being developed to improve the treatment. For example, Klinger et al. [67] used fat injections in severe burn wounds as a trial to improve burn wound healing in humans. They did get results showing scar improvement and enhancement of tissue regeneration, but their study was limited to a small population [67]. In other studies, Auxenfans et al. [68] investigated the role of keratinocytes in improving wound healing in burns. They reported that keratinocytes induced a more rapid burn wound healing [68]. On the other hand, stromal vascular fraction has been also shown to play a possible role in enhancing burn wound healing [69]. Atalay et al. used isolated stromal vascular fraction in burn wound healing. It stimulated an increase in vascular endothelial growth factor and reduced the inflammation with an improved fibroblastic activity [69]. Additionally, Hussein et al. [70] studied the effect of Botox injections on burn wounds healing and found that Botox increased fibroblasts, TGF-B, and TNF-alpha levels and decreased inflammation, thus improving burn wound healing. Another recent study by Zhang et al. [71] showed a beneficial effect of heat shock protein 90 alpha on burn wound healing. It promoted faster healing and less inflammation. In addition, several other studies have examined the effects of different factors and substances such as curcumin, mast cell chymase, and phenytoin with hypericin on burn wound healing with promising results and better wound healing [7274].

Stem cells are commonly derived either from bone marrow, umbilical cord, adipose tissue, or skin. Natesan et al. [75] have even used debrided skin from severe burns as a source of stem cells for wound healing and regeneration. Hence, the adipose tissue that is discarded from burn wound debridement may now be of use for better wound healing. In addition, Natesan et al. [76], in another study, used isolated stem cells from debrided skin with fibrin and collagen based scaffolds. The dermal equivalents, created in the study, decreased wound contraction leading to a better matrix deposition and epithelialization [76]. Along the same line, van der Veen et al. [77] isolated mesenchymal stem cells from excised burn wound eschar. These stem cells showed similar abilities to adipose derived stem cells in differentiating into osteocytes, chondroblasts, and adipocytes [77].

A relatively recent approach by Li et al. [78] studied the role of electric fields in the migration of stem cells. They proved that epithelial stem cells migrate to the cathode in an induced electric field, knowing that endogenous electric fields exist naturally in wounds [78]. The migration of the stem cells was found to be proportional to the strength of the electric field and its duration, with the involvement of epidermal growth factor receptor and mitogen activated protein kinase-PI3K [78]. Hence, in addition to the use of stem cells in burn wounds, electric fields can be applied to the wounds to better direct their migration [78].

The role of stem cells in wound healing has been shown to be performed through several pathways, such as JNK and ERK59, and with the involvement of different factors and mediators, such as KGF-1 and PDGF-BB [5, 8]. Additionally, this role could also be carried out by the released factors and not only by direct integration of the stem cells into the wound scaffold or matrix [6].

Stem cells in burn wound healing have been found to follow the same mechanisms. The increased levels of stem cells in burn wounds suggested a possible enhancing role in aiding in the healing process [9, 10, 12, 13]. However, a lack of consistency of the outcome was documented. Different experiments may have used different amounts of purified stem cells, or stem cells at different stages of replication or differentiation in vitro, leading to what may seem different results. In brief, this review depicted the improved healing with stem cells qualitatively rather than quantitatively. To really demonstrate the value of different stem cells in the process of burn wound healing, more studies need to be done under optimal and well controlled conditions, aiming to measure a quantifiable improvement. Additionally, the excess use of stem cells may lead to unwanted results, such as increased fibrosis and thicker healed epithelium. Whether the effect is observed as a result of direct stem cell proliferation, or other induced substances and cells, needs to be studied in the future. Moreover, the role of cytokines released by stem cells along with bioactive peptides such as thymosin 4 has been documented to mediate the beneficial effect of the stem cell application in burn wound healing. Further data refer the superior healing probably not to the direct integration of the stem cells into the wound [11, 13]. Acute wound fluids were also shown to have a role in promoting faster healing of burn wounds, similarly reinforcing the role of mediators released by stem cells. Additionally, human alpha defensin 5 and the CXCL12/CXCR4 pathway with its signal SDF-1a were found to be inducers of stem cells in burn wounds [16, 18, 20].

In addition, stem cells have been shown to decrease cell infiltration, wound contraction, fibrosis, scar progression, and inflammation of burn wounds. Moreover, they have been found to promote faster burn wound healing and angiogenesis along with better granulation and the formation of hair follicles and sebaceous glands [15, 2245]. The studies reviewed showed positive results in both animal experiments and human trials, both in partial and full thickness injury burns. In addition, different ways of stem cell application have been used ranging from using stem cell scaffolds to systemic and intradermal injection [23, 25, 32]. Furthermore, the sources of stem cells used are multiple. They are derived from bone marrow, dermis, adipose tissue, and umbilical cords, among others [22, 23, 33, 41]. Stem cells have proved to be efficient not only in skin burns but also in corneal chemical burns, thus increasing the multiplicity of their use [5461].

Patients with burn wounds, especially those severely injured, tend to have lower quality of life [79]. The injury they suffer is not only physical but also psychological, affecting their jobs and relations with other people, especially their families [80, 81]. With the advance of burn wound treatment with time, patients self-esteem and quality of life have been improving [82, 83]. The hope is that the use of stem cells will open up a new arena of possibilities to improve the wound healing in burn patients, allowing patients to have faster healing, better scars, and a higher quality of life.

Stem cells have attracted many controversial public opinions over time. Many people argue that embryonic stem cell harvesting would be done by killing embryos which would be unethical [84]. Others would argue that even if embryos are used for stem cell research, it is not wrong. However, the path that this may lead to would be wrong such as embryo production for research purposes [84]. The public view towards the therapeutic use of stem cells has become more tolerant over time [85]. The role of educating people about the colossal potential for the use of stem cell has thus proven beneficial. People are now more educated about the different sources of stem cells and have become supportive of their use [85]. Regarding the acceptance of stem cells as an efficient therapy for burn wound healing in specific, a study done by Clover et al. [86] showed a very positive opinion. The biggest majority of people were willing to accept autologous stem cells, though a big percentage was also welcoming the idea of using allogeneic stem cells. These percentages did not differ between the use of stem cells for burn wounds or for the treatment of other diseases such as diabetes or Parkinsons [86].

In brief, the use of stem cells in burn wound healing appears to be very promising. While most studies were performed on animals, the application to humans is yet at its start. Hence, what is needed is more studies. Additionally, the signaling pathways followed by stem cells involved in the burn wound healing along with their factors and signals constitute a very dynamic and promising research field.

The authors declare that there is no conflict of interests regarding the publication of this paper.

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The Use of Stem Cells in Burn Wound Healing: A Review - Hindawi

Stem cell transplants are used to give back stem cells when the bone marrow has been destroyed by disease, chemotherapy (chemo), or radiation. Depending on where the stem cells come from, the transplant procedure may be called:

They can all be called hematopoietic stem cell transplants.

In a typical stem cell transplant for cancer, very high doses of chemo are used, sometimes along with radiation therapy, to try to kill all the cancer cells. This treatment also kills the stem cells in the bone marrow. This is called myeloablation or myeloablative therapy. Soon after treatment, stem cells are given (transplanted) to replace those that were destroyed. The replacement stem cells are given into a vein, much like ablood transfusion. The goal is that over time, the transplanted cells settle in the bone marrow, begin to grow and make healthy blood cells. This process is called engraftment.

There are 2 main types of transplants. They are named based on who donates the stem cells.

In this type of transplant, the first step is to remove or harvest your own stem cells. Your stem cells are removed from either your bone marrow or your blood, and then frozen. (You can learn more about this process at Whats It Like to Donate Stem Cells?) After you get high doses of chemo and/or radiation as your myeloablative therapy, the stem cells are thawed and given back to you.

Benefits of autologous stem cell transplant: One advantage of autologous stem cell transplant is that youre getting your own cells back. When you get your own stem cells back, you dont have to worry about them (called the engrafted cells or the graft) being rejected by your body.

Risks of autologous stem cell transplant: The grafts can still fail, which means the transplanted stem cells dont go into the bone marrow and make blood cells like they should. Also, autologous transplants cant produce the graft-versus-cancer effect. A possible disadvantage of an autologous transplant is that cancer cells might be collected along with the stem cells and then later put back into your body. Another disadvantage is that your immune system is the same as it was before your transplant. This means the cancer cells were able to escape attack from your immune system before, and may be able to do so again.

This kind of transplant is mainly used to treat certain leukemias, lymphomas, and multiple myeloma. Its sometimes used for other cancers, like testicular cancer and neuroblastoma, and certain cancers in children. Doctors can use autologous transplants for other diseases, too, like systemic sclerosis, multiple sclerosis (MS), and systemic lupus erythematosis (lupus).

To help prevent any remaining cancer cells from being transplanted along with stem cells, some centers treat the stem cells before theyre given back to the patient. This may be called purging. While this might work for some patients, there haven't been enough studies yet to know if this is really a benefit. A possible downside of purging is that some normal stem cells can be lost during this process. This may cause your body to take longer to start making normal blood cells, and you might have very low and unsafe levels of white blood cells or platelets for a longer time. This could increase the risk of infections or bleeding problems.

Another treatment to help kill cancer cells that might be in the returned stem cells involves giving anti-cancer drugs after the transplant. The stem cells are not treated. After transplant, the patient gets anti-cancer drugs to get rid of any cancer cells that may be in the body. This is called in vivo purging. For instance, lenalidomide (Revlimid) may be used in this way for multiple myeloma. The need to remove cancer cells from transplanted stem cells or transplant patients and the best way to do it continues to be researched.

Doing 2 autologous transplants in a row is known as a tandem transplant or a double autologous transplant. In this type of transplant, the patient gets 2 courses of high-dose chemo as myeloablative therapy, each followed by a transplant of their own stem cells. All of the stem cells needed are collected before the first high-dose chemo treatment, and half of them are used for each transplant. Usually, the 2 courses of chemo are given within 6 months. The second one is given after the patient recovers from the first one.

Tandem transplants have become the standard of care for certain cancers. High-risk types of the childhood cancer neuroblastoma and adult multiple myeloma are cancers where tandem transplants seem to show good results. But doctors dont always agree that these are really better than a single transplant for certain cancers. Because this treatment involves 2 transplants, the risk of serious outcomes is higher than for a single transplant.

Sometimes an autologous transplant followed by an allogeneic transplant might also be called a tandem transplant. (See Mini-transplants below.)

Allogeneic stem cell transplants use donor stem cells. In the most common type of allogeneic transplant, the stem cells come from a donor whose tissue type closely matches yours. (This is discussed in Matching patients and donors.) The best donor is a close family member, usually a brother or sister. If you dont have a good match in your family, a donor might be found in the general public through a national registry. This is sometimes called a MUD (matched unrelated donor) transplant. Transplants with a MUD are usually riskier than those with a relative who is a good match.

An allogeneic transplant works about the same way as an autologous transplant. Stem cells are collected from the donor and stored or frozen. After you get high doses of chemo and/or radiation as your myeloablative therapy, the donor's stem cells are thawed and given to you.

Blood taken from the placenta and umbilical cord of newborns is a type of allogeneic transplant. This small volume of cord blood has a high number of stem cells that tend to multiply quickly. Cord blood transplants are done for both adults and children. By 2017, an estimated 700,000 units (batches) of cord blood had been donated for public use. And, even more have been collected for private use. In some studies, the risk of a cancer not going away or coming back after a cord blood transplant was less than after an unrelated donor transplant.

Benefits of allogeneic stem cell transplant: The donor stem cells make their own immune cells, which could help kill any cancer cells that remain after high-dose treatment. This is called the graft-versus-cancer or graft-versus-tumor effect. Other advantages are that the donor can often be asked to donate more stem cells or even white blood cells if needed, and stem cells from healthy donors are free of cancer cells.

Risks of allogeneic stem cell transplants: The transplant, or graft, might not take that is, the transplanted donor stem cells could die or be destroyed by the patients body before settling in the bone marrow. Another risk is that the immune cells from the donor may not just attack the cancer cells they could attack healthy cells in the patients body. This is called graft-versus-host disease. There is also a very small risk of certain infections from the donor cells, even though donors are tested before they donate. A higher risk comes from infections you had previously, and which your immune system has had under control. These infections may surface after allogeneic transplant because your immune system is held in check (suppressed) by medicines called immunosuppressive drugs. Such infections can cause serious problems and even death.

Allogeneic transplant is most often used to treat certain types of leukemia, lymphomas, multiple myeloma, myelodysplastic syndrome, and other bone marrow disorders such as aplastic anemia.

For some people, age or certain health conditions make it more risky to do myeloablative therapy that wipes out all of their bone marrow before a transplant. For those people, doctors can use a type of allogeneic transplant thats sometimes called a mini-transplant. Your doctor might refer to it as a non-myeloablative transplant or mention reduced-intensity conditioning (RIC). Patients getting a mini transplant typically get lower doses of chemo and/or radiation than if they were getting a standard myeloablative transplant. The goal in the mini-transplant is to kill some of the cancer cells (which will also kill some of the bone marrow), and suppress the immune system just enough to allow donor stem cells to settle in the bone marrow.

Unlike the standard allogeneic transplant, cells from both the donor and the patient exist together in the patients body for some time after a mini-transplant. But slowly, over the course of months, the donor cells take over the bone marrow and replace the patients own bone marrow cells. These new cells can then develop an immune response to the cancer and help kill off the patients cancer cells the graft-versus-cancer effect.

One advantage of a mini-transplant is that it uses lower doses of chemo and/or radiation. And because the stem cells arent all killed, blood cell counts dont drop as low while waiting for the new stem cells to start making normal blood cells. This makes it especially useful for older patients and those with other health problems. Rarely, it may be used in patients who have already had a transplant.

Mini-transplants treat some diseases better than others. They may not work well for patients with a lot of cancer in their body or people with fast-growing cancers. Also, although there might be fewer side effects from chemo and radiation than those from a standard allogeneic transplant, the risk of graft-versus-host disease is the same. Some studies have shown that for some cancers and some other blood conditions, both adults and children can have the same kinds of results with a mini-transplant as compared to a standard transplant.

This is a special kind of allogeneic transplant that can only be used when the patient has an identical sibling (twin or triplet) someone who has the exact same tissue type. An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. Also, there are no cancer cells in the transplanted stem cells, as there might be in an autologous transplant.

A disadvantage is that because the new immune system is so much like the recipients immune system, theres no graft-versus-cancer effect. Every effort must be made to destroy all the cancer cells before the transplant is done to help keep the cancer from coming back.

Improvements have been made in the use of family members as donors. This kind of transplant is called ahalf-match (haploidentical) transplant for people who dont have fully matching or identical family member. This can be another option to consider, along with cord blood transplant and matched unrelated donor (MUD) transplant.

If possible, it is very important that the donor and recipient are a close tissue match to avoid graft rejection. Graft rejection happens when the recipients immune system recognizes the donor cells as foreign and tries to destroy them as it would a bacteria or virus. Graft rejection can lead to graft failure, but its rare when the donor and recipient are well matched.

A more common problem is that when the donor stem cells make their own immune cells, the new cells may see the patients cells as foreign and attack their new home. This is called graft-versus-host disease. (See Stem Cell Transplant Side Effects for more on this). The new, grafted stem cells attack the body of the person who got the transplant. This is another reason its so important to find the closest match possible.

Many factors play a role in how the immune system knows the difference between self and non-self, but the most important for transplants is the human leukocyte antigen (HLA) system. Human leukocyte antigens are proteins found on the surface of most cells. They make up a persons tissue type, which is different from a persons blood type.

Each person has a number of pairs of HLA antigens. We inherit them from both of our parents and, in turn, pass them on to our children. Doctors try to match these antigens when finding a donor for a person getting a stem cell transplant.

How well the donors and recipients HLA tissue types match plays a large part in whether the transplant will work. A match is best when all 6 of the known major HLA antigens are the same a 6 out of 6 match. People with these matches have a lower chance of graft-versus-host disease, graft rejection, having a weak immune system, and getting serious infections. For bone marrow and peripheral blood stem cell transplants, sometimes a donor with a single mismatched antigen is used a 5 out of 6 match. For cord blood transplants a perfect HLA match doesnt seem to be as important, and even a sample with a couple of mismatched antigens may be OK.

Doctors keep learning more about better ways to match donors. Today, fewer tests may be needed for siblings, since their cells vary less than an unrelated donor. But to reduce the risks of mismatched types between unrelated donors, more than the basic 6 HLA antigens may be tested. For example, sometimes doctors to try and get a 10 out of 10 match. Certain transplant centers now require high-resolution matching, which looks more deeply into tissue types and allow more specific HLA matching.

There are thousands of different combinations of possible HLA tissue types. This can make it hard to find an exact match. HLA antigens are inherited from both parents. If possible, the search for a donor usually starts with the patients brothers and sisters (siblings), who have the same parents as the patient. The chance that any one sibling would be a perfect match (that is, that you both received the same set of HLA antigens from each of your parents) is 1 out of 4.

If a sibling is not a good match, the search could then move on to relatives who are less likely to be a good match parents, half siblings, and extended family, such as aunts, uncles, or cousins. (Spouses are no more likely to be good matches than other people who are not related.) If no relatives are found to be a close match, the transplant team will widen the search to the general public.

As unlikely as it seems, its possible to find a good match with a stranger. To help with this process, the team will use transplant registries, like those listed here. Registries serve as matchmakers between patients and volunteer donors. They can search for and access millions of possible donors and hundreds of thousands of cord blood units.

Be the Match (formerly the National Marrow Donor Program)Toll-free number: 1-800-MARROW-2 (1-800-627-7692)Website: http://www.bethematch.org

Blood & Marrow Transplant Information NetworkToll-free number: 1-888-597-7674Website: http://www.bmtinfonet.org

Depending on a persons tissue typing, several other international registries also are available. Sometimes the best matches are found in people with a similar racial or ethnic background. When compared to other ethnic groups, white people have a better chance of finding a perfect match for stem cell transplant among unrelated donors. This is because ethnic groups have differing HLA types, and in the past there was less diversity in donor registries, or fewer non-White donors. However, the chances of finding an unrelated donor match improve each year, as more volunteers become aware of registries and sign up for them.

Finding an unrelated donor can take months, though cord blood may be a little faster. A single match can require going through millions of records. Also, now that transplant centers are more often using high-resolution tests, matching is becoming more complex. Perfect 10 out of 10 matches at that level are much harder to find. But transplant teams are also getting better at figuring out what kinds of mismatches can be tolerated in which particular situations that is, which mismatched antigens are less likely to affect transplant success and survival.

Keep in mind that there are stages to this process there may be several matches that look promising but dont work out as hoped. The team and registry will keep looking for the best possible match for you. If your team finds an adult donor through a transplant registry, the registry will contact the donor to set up the final testing and donation. If your team finds matching cord blood, the registry will have the cord blood sent to your transplant center.

Read more:
Types of Stem Cell and Bone Marrow Transplants - American Cancer Society

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into various types of cells including skeletal muscle cells. The approach of converting ESCs/iPSCs into skeletal muscle cells offers hope for patients afflicted with the skeletal muscle diseases such as the Duchenne muscular dystrophy (DMD). Patient-derived iPSCs are an especially ideal cell source to obtain an unlimited number of myogenic cells that escape immune rejection after engraftment. Currently, there are several approaches to induce differentiation of ESCs and iPSCs to skeletal muscle. A key to the generation of skeletal muscle cells from ESCs/iPSCs is the mimicking of embryonic mesodermal induction followed by myogenic induction. Thus, current approaches of skeletal muscle cell induction of ESCs/iPSCs utilize techniques including overexpression of myogenic transcription factors such as MyoD or Pax3, using small molecules to induce mesodermal cells followed by myogenic progenitor cells, and utilizing epigenetic myogenic memory existing in muscle cell-derived iPSCs. This review summarizes the current methods used in myogenic differentiation and highlights areas of recent improvement.

Duchenne muscular dystrophy (DMD) is a genetic disease affecting approximately 1 in 3500 male live births [1]. It results in progressive degeneration of skeletal muscle causing complete paralysis, respiratory and cardiac complications, and ultimately death. Normal symptoms include the delay of motor milestones including the ability to sit and stand independently. DMD is caused by an absence of functional dystrophin protein and skeletal muscle stem cells, as well as the exhaustion of satellite cells following many rounds of muscle degeneration and regeneration [2]. The dystrophin gene is primarily responsible for connecting and maintaining the stability of the cytoskeleton of muscle fibers during contraction and relaxation. Despite the low frequency of occurrence, this disease is incurable and will cause debilitation of the muscle and eventual death in 20 to 30 year olds with recessive X-linked form of muscular dystrophy. Although there are no current treatments developed for DMD, there are several experimental therapies such as stem cell therapies.

Skeletal muscle is known to be a regenerative tissue in the body. This muscle regeneration is mediated by muscle satellite cells, a stem cell population for skeletal muscle [3, 4]. Although satellite cells exhibit some multipotential differentiation capabilities [5], their primary differentiation fate is skeletal muscle cells in normal muscle regeneration. Ex vivo expanded satellite cell-derived myoblasts can be integrated into muscle fibers following injection into damaged muscle, acting as a proof-of-concept of myoblast-mediated cell therapy for muscular dystrophies [69]. However, severe limitations exist in relation to human therapy. The number of available satellite cells or myoblasts from human biopsies is limited. In addition, the poor cell survival and low contribution of transplanted cells have hindered practical application in patients [6, 8, 9]. Human-induced pluripotent stem cells (hiPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell- (ESC-) like state by being forced to express genes and factors important for maintaining the defining properties of ESCs. hiPSCs can be generated from a wide variety of somatic cells [10, 11]. They have the ability to self-renew and successfully turn into any type of cells. With their ability to capture genetic diversity of DMD in an accessible culture system, hiPSCs represent an attractive source for generating myogenic cells for drug screening.

The ESC/iPSC differentiation follows the steps of embryonic development. The origin of skeletal muscle precursor cells comes from the mesodermal lineage, which give rise to skeletal muscle, cardiac muscle, bone, and blood cells. Mesoderm subsequently undergoes unsegmented presomitic mesoderm followed by segmented compartments termed somites from anterior to caudal direction. Dermomyotome is an epithelial cell layer making up the dorsal part of the somite underneath the ectoderm. Dermomyotome expresses Pax3 and Pax7 and gives rise to dermis, skeletal muscle cells, endothelial cells, and vascular smooth muscle [12]. Dermomyotome also serves as a tissue for secreted signaling molecules to the neural tube, notochord, and sclerotome [13, 14]. Upon signals from the neural tube and notochord, the dorsomedial lip of dermomyotome initiates and expresses skeletal muscle-specific transcription factors such as MyoD and Myf5 to differentiate into myogenic cells termed myoblasts. Myoblasts then migrate beneath the dermomyotome to form myotome. Eventually, these myoblasts fuse with each other to form embryonic muscle fibers. ESCs/iPSCs mimic these steps toward differentiation of skeletal muscle cells. Many studies utilize methods of overexpression of muscle-related transcription factors such as MyoD or Pax3 [15], or the addition of small molecules which activate or inhibit myogenic signaling during development. Several studies show that iPSCs retain a bias to form their cell type of origin due to an epigenetic memory [1619], although other papers indicate that such epigenetic memory is erased during the reprogramming processes [2022]. Therefore, this phenomenon is not completely understood at the moment. In light of these developments, we have recently established mouse myoblast-derived iPSCs capable of unlimited expansion [23]. Our data demonstrates that these iPSCs show higher myogenic differentiation potential compared to fibroblast-derived iPSCs. Thus, myogenic precursor cells generated from human myoblast-derived iPSCs expanded ex vivo should provide an attractive cell source for DMD therapy. However, since DMD is a systemic muscle disease, systemic delivery of myoblasts needs to be established for efficient cell-based therapy.

During developmental myogenesis, presomitic mesoderm is first formed by Mesogenin1 upregulation, which is a master regulator of presomitic mesoderm [24]. Then, the paired box transcription factor Pax3 gene begins to be expressed from presomitic mesoderm to dermomyotome [25]. Following Pax3 expression, Pax7 is also expressed in the dermomyotome [26], and then Myf5 and MyoD, skeletal muscle-specific transcription factor genes, begin to be expressed in the dorsomedial lip of the dermomyotome in order to give rise to myoblasts which migrate beneath the dermomyotome to form the myotome. Subsequently, Mrf4 and Myogenin, other skeletal muscle-specific transcription factor genes, followed by skeletal muscle structural genes such as myosin heavy chain (MyHC), are expressed in the myotome for myogenic terminal differentiation (Figure 1) [27, 28]. Pax3 directly and indirectly regulates Myf5 expression in order to induce myotomal cells. Dorsal neural tube-derived Wnt proteins and floor plate cells in neural tube and notochord-derived sonic hedgehog (Shh) positively regulate myotome formation [13, 29]. Neural crest cells migrating from dorsal neural tubes are also involved in myotome formation: Migrating neural crest cells come across the dorsomedial lip of the dermomyotome, and neural crest cell-expressing Delta1 is transiently able to activate Notch1 in the dermomyotome, resulting in conversion of Pax3/7(+) myogenic progenitor cells into MyoD/Myf5(+) myotomal myoblasts [30, 31]. By contrast, bone morphogenetic proteins (BMPs) secreted from lateral plate mesoderm are a negative regulator for the myotome formation by maintaining Pax3/Pax7(+) myogenic progenitor cells [29, 32]. Pax3 also regulates cell migration of myogenic progenitor cells from ventrolateral lip of dermomyotome to the limb bud [33]. Pax3 mutant mice lack limb muscle but trunk muscle development is relatively normal [34]. Pax3/Pax7 double knockout mice display failed generation of myogenic cells, suggesting that Pax3 and Pax7 are critical for proper embryonic myogenesis [35]. Therefore, both Pax3 and Pax7 are also considered master transcription factors for the specification of myogenic progenitor cells. Importantly, MyoD was identified as the first master transcription factor for myogenic specification since MyoD is directly able to reprogram nonmuscle cell type to myogenic lineage when overexpressed [3638]. In addition, genetic ablation of MyoD family gene(s) via a homologous gene recombination technique causes severe myogenic developmental or regeneration defects [3945]. Finally, genetic ablation of combinatory MyoD family genes demonstrates that MyoD/:Myf5/:MRF4/ mice do not form any skeletal muscle during embryogenesis, indicating the essential roles in skeletal muscle development of MyoD family genes [28, 46]. It was proven that Pax3 also possesses myogenic specification capability since ectopic expression of Pax3 is sufficient to induce myogenic programs in both paraxial and lateral plate mesoderm as well as in the neural tube during chicken embryogenesis [47]. In addition, genetic ablation of Pax3 and Myf5 display complete defects of body skeletal muscle formation during mouse embryogenesis [48]. Finally, overexpression of Pax7 can convert CD45(+)Sca-1(+) hematopoietic cells into skeletal muscle cells [49]. From these notions, overexpression of myogenic master transcription factors such as MyoD or Pax3 has become the major strategy for myogenic induction in nonmuscle cells, including ES/iPSCs.

The overexpression of MyoD approach to induce myogenic cells from mESCs was first described by Dekel et al. in 1992. This has been a standard approach for the myogenic induction from pluripotent stem cells (Table 1). Ozasa et al. first utilized Tet-Off systems for MyoD overexpression in mESCs and showed desmin(+) and MyHC(+) myotubes in vitro [50]. Warren et al. transfected synthetic MyoD mRNA in to hiPSCs for 3 days, which resulted in myogenic differentiation (around 40%) with expression of myogenin and MyHC [51]. Tanaka et al. utilized a PiggyBac transposon system to overexpress MyoD in hiPSCs. The PiggyBac transposon system allows cDNAs to stably integrate into the genome for efficient gene expression. After integration, around 70 to 90% of myogenic cells were induced in hiPSC cultures within 5 days [52]. This study also utilized Miyoshi myopathy patient-derived hiPSCs for the MyoD-mediated myogenic differentiation. Miyoshi myopathy is a congenital distal myopathy caused by defective muscle membrane repair due to mutations in dysferlin gene. The patient-derived hiPSC-myogenic cells will be able to provide the opportunity for therapeutic drug screening. Abujarour et al. also established a model of patient-derived skeletal muscle cells which express NCAM, myogenin, and MyHC by doxycycline-inducible overexpression of MyoD in DMD patient-derived hiPSCs [53]. Interestingly, MyoD-induced iPSCs also showed suppression of pluripotent genes such as Nanog and a transient increase in the gene expression levels of T (Brachyury T), Pax3, and Pax7, which belong to paraxial mesodermal/myogenic progenitor genes, upstream genes of myogenesis. It is possible that low levels of MyoD activity in hiPSCs may initially suppress their pluripotent state while failing to induce myogenic programs, which may result in transient paraxial mesodermal induction. Supporting this idea, BAF60C, a SWI/SNF component that is involved in chromatin remodeling and binds to MyoD, is required to induce full myogenic program in MyoD-overexpressing hESCs [54]. Overexpression of MyoD alone in hESC can only induce some paraxial mesodermal genes such as Brachyury T, mesogenin, and Mesp1 but not myogenic genes. Co-overexpression of MyoD and BAF60C was now able to induce myogenic program but not paraxial mesodermal gene expression, indicating that there are different epigenetic landscapes between pluripotent ESCs/iPSCs and differentiating ESC/iPSCs in which MyoD is more accessible to DNA targets than those in pluripotent cells. The authors then argued that without specific chromatin modifiers, only committed cells give rise to myogenic cells by MyoD. These results strongly indicate that nuclear landscapes are important for cell homogeneity for the specific cell differentiation in ESC/iPSC cultures. Similar observations were seen in overexpression of MyoD in P19 embryonal carcinoma stem cells, which can induce paraxial mesodermal genes including Meox1, Pax3, Pax7, Six1, and Eya2 followed by muscle-specific genes. However, these MyoD-induced paraxial mesodermal genes were mediated by direct MyoD binding to their regulatory regions, which was proven by chromatin immunoprecipitation (ChIP) assays, indicating the novel role for MyoD in paraxial mesodermal cell induction [55].

hESCs/iPSCs have been differentiated into myofibers by overexpression of MyoD, and this method is considered an excellent in vitro model for human skeletal muscle diseases for muscle functional tests, therapeutic drug screening, and genetic corrections such as exon skipping and DNA editing. Shoji et al. have shown that DMD patient-derived iPSCs were used for myogenic differentiation via PiggyBac-mediated MyoD overexpression. These myogenic cells were treated with morpholinos for exon-skipping strategies for dystrophin gene correction and showed muscle functional improvement [56]. Li et al. have shown that patient-derived hiPSC gene correction by TALEN and CRISPR-Cas9 systems, and these genetically corrected hiPSCs were used for myogenic differentiation via overexpression of MyoD [57]. This work also revealed that the TALEN and CRISPR-Cas9-mediated exon 44 knock-in approach in the dystrophin gene has high efficiency in gene-editing methods for DMD patient-derived cells in which the exon 44 is missing in the genome.

Along this line of the strategy, Darabi et al. first performed overexpression of Pax3 gene, which can be activated by treatment with doxycycline in mESCs, and showed efficient induction of MyoD/Myf5(+) skeletal myoblasts in EB cultures [15]. Upon removing doxycycline, these myogenic cells underwent MyHC(+) myotubes. However, teratoma formation was observed after EB cell transplantation into cardiotoxin-injured regenerating skeletal muscle in Rag2/:C/ immunodeficient mice [15]. This indicates that myogenic cell cultures induced by Pax3 in mESCs still contain some undifferentiated cells which gave rise to teratomas. To overcome this problem, the same authors separated paraxial mesodermal cells from Pax3-induced EB cells by FACS using antibodies against cell surface markers as PDGFR(+)Flk-1() cell populations. After cell sorting, isolated Pax3-induced paraxial mesodermal cells were successfully engrafted and contributed to regenerating muscle in mdx:Rag2/:C/ DMD model immunodeficient mice without any teratoma formations. Darabi et al. also showed successful myogenic induction in mESCs and hES/iPSCs by overexpression of Pax7 [58, 59]. Pax3 and Pax7 are not only expressed in myogenic progenitor cells. They are also expressed in neural tube and neural crest cell-derived cells including a part of cardiac cell types in developmental stage, suggesting that further purification to skeletal muscle cell lineage is crucial for therapeutic applications for muscle diseases including DMD.

Taken together, overexpression of myogenic master transcription factors such as MyoD or Pax3/Pax7 is an excellent strategy for myogenic induction in hESCs and hiPSCs, which can be utilized for in vitro muscle disease models for their functional test and drug screening. However, for the safe stem cell therapy, it is essential to maintain the good cellular and genetic qualities of hESC/hiPSC-derived myogenic cells before transplantation. Therefore, random integration sites of overexpression vectors for myogenic master transcription factors and inappropriate expression control of these transgenes may diminish the safety of using these induced myogenic cells for therapeutic stem cell transplantation.

Stepwise induction protocols utilizing small molecules and growth factors have been established as alternative myogenic induction approaches and a more applicable method for therapeutic situations. As described above, during embryonic myogenesis, somites and dermomyotomes receive secreted signals such as Wnts, Notch ligands, Shh, FGF, BMP, and retinoic acid (RA) with morphogen gradients from surrounding tissues in order to induce the formation of myogenic cells (Figure 2). The canonical Wnt signaling pathway has been shown to play essential roles in the development of myogenesis. In mouse embryogenesis, Wnt1 and Wnt3a secreted from the dorsal neural tube can promote myogenic differentiation of dorsomedial dermomyotome via activation of Myf5 [31, 32, 60]. Wnt3a is able to stabilize -catenin which associates with TCF/LEF transcription factors that bind to the enhancer region of Myf5 during myogenesis [61]. Other Wnt proteins, Wnt6 and Wnt7a, which emerge from the surface ectoderm, induce MyoD [62]. BMP functions as an inhibitor of myogenesis by suppression of some myogenic gene expressions. In the lateral mesoderm, BMP4 is able to increase Pax3 expression which delays Myf5 expression in order to maintain an undifferentiated myogenic progenitor state [63]. Therefore, Wnts and BMPs regulate myogenic development by antagonizing each other for myogenic transcription factor gene expression [64, 65]. Wnt also induces Noggin expression to antagonize BMP signals in the dorsomedial lip of the dermomyotome [66]. In this region, MyoD expression level is increased, which causes myotome formation. Notch signaling plays essential roles for cell-cell communication to specify the different cells in developmental stages. During myotome formation, Notch is expressed in dermomyotome, and Notch1 and Notch2 are expressed in dorsomedial lip of dermomyotome. Delta1, a Notch ligand, is expressed in neural crest cells which transiently interact with myogenic progenitor cells in dorsomedial lip of dermomyotome via Notch1 and 2. This contact induces expression of the Myf5 or MyoD gene in the myogenic progenitor cells followed by myotome formation. The loss of function of Delta1 in the neural crest displays delaying skeletal muscle formation [67]. Knockdown of Notch genes or use of a dominant-negative form of mastermind, a Notch transcriptional coactivator, clearly shows dramatically decrease of Myf5 and MyHC(+) myogenic cells. Interestingly, induction of Notch intracellular domain (NICD), a constitutive active form of Notch, can promote myogenesis, while continuous expression of NICD prevents terminal differentiation. Taken together, transient and timely activation of Notch is crucial for myotome formation from dermomyotome [30].

Current studies for myogenic differentiation of ESCs/iPSCs have utilized supplementation with some growth factors and small molecules, which would mimic the myogenic development described above in combination with embryoid body (EB) aggregation and FACS separation of mesodermal cells (Table 2). To induce paraxial mesoderm cells from mESCs, Sakurai et al. utilized BMP4 in serum-free cultures [68]. Three days after treatment with BMP4, mESCs could be differentiated into primitive streak mesodermal-like cells, but the continuous treatment with BMP4 turned the ESCs into osteogenic cells. Therefore, they used LiCl after treatment with BMP4 to enhance Wnt signaling, which is able to induce myogenic differentiation. After treatment with LiCl, PDGFR(+) E-cadherin() paraxial mesodermal cells were sorted by FACS. These sorted cells were cultured with IGF, HGF, and FGF for two weeks in order to induce myogenic differentiation. Hwang et al. have shown that treatment with Wnt3a efficiently promotes skeletal muscle differentiation of hESCs [69]. hESCs were cultured to form EB for 9 days followed by differentiation of EBs for additional 7 days, and then PDGFR(+) cells were sorted by FACS. These PDGFR(+) cells were cultured with Wnt3a for additional 14 days. Consequently, these Wnt3a-treated cells display significantly increased myogenic transcription factors and structural proteins at both mRNA and protein levels. An interesting approach to identify key molecules that induce myogenic cells was reported by Xu et al. [70]. They utilized reporter systems in zebrafish embryos to display myogenic progenitor cell induction and myogenic differentiation in order to identify small compounds for myogenic induction. Myf5-GFP marks myogenic progenitor cells, while myosin light polypeptide 2 (mylz2)-mCherry marks terminally differentiated muscle cells. They found that a mixed cocktail containing GSK3 inhibitor, bFGF, and forskolin has the potential to induce robust myogenic induction in hiPSCs. GSK3 inhibitors act as a canonical Wnt signaling activator via stabilizing -catenin protein, which is crucial for inducing mesodermal cells. Forskolin activates adenylyl cyclase, which then stimulates cAMP signaling. cAMP response element-binding protein (CREB) is able to stimulate cell proliferation of primary myoblasts in vitro, suggesting that the forskolin-cAMP-CREB pathway may help myogenic cell expansion [71], However the precise mechanisms for CREB-mediated myogenic cell expansion remain unclear. The adenylyl cyclase signaling cascade leads to CREB activation [71]. During embryogenesis, phosphorylated CREB has been found at dorsal somite and dermomyotome. CREB gene knockout mice display significantly decreased Myf5 and MyoD expressions in myotomes. While activation of Wnt1 or Wnt7a promotes Pax3, Myf5, and MyoD expressions, inhibition of CREB eliminates these Wnt-mediated myogenic gene expressions without altering the Wnt canonical pathway, suggesting that CREB-induced myogenic activation may be mediated through noncanonical Wnt pathways. Several groups also utilized GSK3 inhibitors for inducing mesodermal cells from ESCs and iPSCs [72, 73]. These mesodermal cell-like cells were expanded by treatment with bFGF, and then ITS (insulin/transferrin/selenite) or N2 medium were used to induce myogenic differentiation. Finally, bFGF is a stimulator for myogenic cell proliferation. Caron et al. demonstrated that hESCs treated with GSK3 inhibitor, ascorbic acid, Alk5 inhibitor, dexamethasone, EGF, and insulin generated around 80% of Pax3(+) myogenic precursor cells in 10 days [74]. Treatment with SB431542, an inhibitor of Alk4, 5, and 7, PDGF, bFGF, oncostatin, and IGF was able to induce these Pax3(+) myogenic precursor cells into around 5060% of MyoD(+) myoblasts in an additional 8 days. For the final step, treatment with insulin, necrosulfonamide, an inhibitor of necrosis, oncostatin, and ascorbic acid was able to induce these myoblasts into myotubes in an additional 8 days. Importantly, the same authors utilized ESCs from human facioscapulohumeral muscular dystrophy (FSHD) to demonstrate the myogenic characterization after myogenic induction by using the protocol described above. Hosoyama et al. have shown that hESCs/iPSCs with high concentrations of bFGF and EGF in combination with cell aggregation, termed EZ spheres, efficiently give rise to myogenic cells [75]. After 6-week culture, around 4050% of cells expressed Pax7, MyoD, or myogenin. However, the authors also showed that EZ spheres included around 30% of Tuj1(+) neural cells. Therefore, the authors discussed the utilization of molecules for activation of mesodermal and myogenic signaling pathways such as BMPs and Wnts.

Taken together, it is likely that the induced cell populations from ESCs/iPSCs may contain other cell types such as neural cells or cardiac cells because neural cells share similar transcription factor gene expression with myogenic cells such as Pax3, and cardiac cells also develop from mesodermal cells. To overcome this limitation, Chal et al. treated ESCs/iPSCs with BMP4 inhibitor, which prevents ESCs/iPSCs from differentiating into lateral mesodermal cells [76, 77]. To identify what genes are involved in myogenic differentiation in vivo, they performed a microarray analysis which compared samples of dissected fragments in mouse embryos, which are able to separate tail bud, presomitic mesoderm, and somite regions. From microarray data, the authors focused on Mesogenin1 (Msgn1) and Pax3 genes. Importantly, they utilized three lineage tracing reporters, Msgn1-repV (Mesogenin1-Venus) marking posterior somitic mesoderm, Pax3-GFP marking anterior somitic mesoderm and myogenic cells, and Myog-repV (Myogenin-Venus) marking differentiated myocytes, allowing the authors to readily detect different differentiation stages during ESC/iPSC cultures. Treatment with GSK3 inhibitors and then BMP inhibitors in ESC cultures induced Msgn1(+) somitic mesoderm with 45 to 65% efficiencies, Pax3(+) anterior somitic mesoderm with 30 to 50% efficiencies, and myogenin(+) myogenic cells with 25 to 30% efficiencies. Furthermore, the authors examined differentiation of mdx ESCs into skeletal muscle cells and revealed abnormal branching myofibers. Current protocols were also published and described more details for hiPSC differentiation [77].

Some nonmuscle cell populations such as mesoangioblasts have the potential to differentiate into skeletal muscle [6]. Mesoangioblasts were originally isolated from embryonic mouse dorsal aorta as vessel-associated pericyte-like cells, which have the ability to differentiate into a myogenic lineage in vitro and in vivo [6, 78]. Mesoangioblasts possess an advantage for the clinical cell-based treatment because they can be injected through an intra-arterial route to systemically deliver cells, which is crucial for therapeutic cell transplantation for muscular dystrophies [79]. Tedesco et al. successfully generated human iPSC-derived mesoangioblast-like stem/progenitor cells called HIDEMs by stepwise protocols without FACS sorting [80, 81]. They displayed similar gene expression profiles as embryonic mesoangioblasts. However, HIDEMs do not spontaneously differentiate into skeletal muscle cells, and thus, the authors utilized overexpression of MyoD to differentiate into skeletal muscle cells. Similar to mesoangioblasts, HIDEM-derived myogenic cells could be delivered to injured muscle via intramuscular and intra-arterial routes. Furthermore, HIDEMs have been generated from hiPSCs derived from limb-girdle muscular dystrophy (LGMD) type 2D patients and used for gene correction and cell transplantation experiments for the potential therapeutic application.

Myogenic precursor cells derived from ESCs/iPSCs by various methods may contain nonmuscle cells. Therefore, further purification is mandatory for therapeutic applications. Barberi et al. isolated CD73(+) multipotent mesenchymal precursor cells from hESCs by FACS, and these cells underwent differentiation into fat, cartilage, bone, and skeletal muscle cells [82]. Barberi et al. also demonstrated that hESCs cultured on OP9 stroma cells generated around 5% of CD73(+) adult mesenchymal stem cell-like cells [83]. After FACS, these CD73(+) mesenchymal stem cell-like cells were cultured with ITS medium for 4 weeks and then gave rise to NCAM(+) myogenic cells. After FACS sorting, these NCAM(+) myogenic cells were purified by FACS and transplanted into immunodeficient mice to show their myogenic contribution to regenerating muscle.

It has been shown that many genes are associated with myogenesis. In addition, exhaustive analysis, such as microarray, RNA-seq, and single cell RNA-seq supplies much gene information in many different stages. Chal et al. showed key signaling factors by microarray from presomitic somite, somite, and tail bud cells [76]. They found that initial Wnt signaling has important roles for somite differentiation. Furthermore, mapping differentiated hESCs by single cell RNA-seq analysis is useful to characterize each differentiated stage [84].

As shown above, cell sorting of mesodermal progenitor cells, mesenchymal precursor cells, or myogenic cells is a powerful tool to obtain pure myogenic populations from differentiated pluripotent cells. Sakurai et al. have been able to induce PDGFR(+)Flk-1() mesodermal progenitor cells by FACS followed by myogenic differentiation [85]. Chang et al. and Mizuno et al. have been able to sort SMC-2.6(+) myogenic cells from mouse ESCs/iPSCs [86, 87]. These SMC-2.6(+) myogenic cells were successfully engrafted into mouse regenerating skeletal muscle. However, this SMC-2.6 antibody only recognizes mouse myogenic cells but not human myogenic cells [86, 88]. Therefore, Borchin et al. have shown that hiPSC-derived myogenic cells differentiated into c-met(+)CXCR4(+)ACHR(+) cells, displaying that over 95% of sorted cells are Pax7(+) myogenic cells [72]. Taken together, current myogenic induction protocols utilizing small molecules and growth factors, with or without myogenic transcription factors, have been largely improved in the last 5 years. It is crucial to standardize the induction protocols in the near future to obtain sufficient myogenic cell conversion from pluripotent stem cells.

Recent work demonstrated that cells inherit a stable genetic program partly through various epigenetic marks, such as DNA methylation and histone modifications. This cellular memory needs to be erased during genetic reprogramming, and the cellular program reverted to that of an earlier developmental stage [16, 22, 89]. However, iPSCs retaining an epigenetic memory of their origin can readily differentiate into their original tissues [1619, 90100]. This phenomenon becomes a double-edged sword for the reprogramming process since the retention of epigenetic memory may reduce the quality of pluripotency while increasing the differentiation efficiency into their original tissues. DNA methylation levels are relatively low in the pluripotent stem cells compared to the high levels of DNA methylation seen in somatic cells [101]. Global DNA demethylation is required for the reprogramming process [102]. In the context of these observations, recent work demonstrates that activation-induced cytidine deaminase AID/AICDA contributing to the DNA demethylation can stabilize stem-cell phenotypes by removing epigenetic memory of pluripotent genes. This directly deaminates 5-methylcytosine in concert with base-excision repair to exchange cytosine in genomic DNA [103]. MicroRNA-155 has been identified as a key player for the retention of epigenetic memory during in vitro differentiation of hematopoietic progenitor cell-derived iPSCs toward hematopoietic progenitors [104]. iPSCs that maintained high levels of miR-155 expression tend to differentiate into the original somatic population more efficiently.

Recently, we generated murine skeletal muscle cell-derived iPSCs (myoblast-derived iPSCs) [23] and compared the efficiency of differentiation of myogenic progenitor cells between myoblast-derived iPSCs and fibroblast-derived iPSCs. After EB cultures, more satellite cell/myogenic progenitor cell differentiation occurred in myoblast-derived iPSCs than that in fibroblast-derived-iPSCs (unpublished observation and Figure 3), suggesting that myoblast-derived iPSCs are potential myogenic and satellite cell sources for DMD and other muscular dystrophy therapies (Figure 4). We also noticed that MyoD gene suppression by Oct4 is required for reprogramming in myoblasts to produce iPSCs (Figure 3) [23]. During overexpression of Oct4, Oct4 first binds to the Oct4 consensus sequence located in two MyoD enhancers (a core enhancer and distal regulatory region) [105107] preceding occupancy at the promoter in myoblasts in order to suppress MyoD gene expression. Interestingly, Oct4 binding to the MyoD core enhancer allows for establishment of a bivalent state in MyoD promoter as a poised state, marked by active (H3K4me3) and repressive (H3K27me3) modifications in fibroblasts, one of the characteristics of stem cells (Figure 3) [23, 108]. It should be investigated whether the similar bivalent state is also established in Oct4-expressing myoblasts during reprogramming process from myoblasts to pluripotent stem cells. It remains to be elucidated whether Oct4-mediated myogenic repression only relies on repression of MyoD expression or is just a general phenomenon of functional antagonism between Oct4 and MyoD on activation of muscle genes. Nevertheless, myoblast-derived iPSCs will enable us to produce an unlimited number of myogenic cells, including satellite cells that could form the basis of novel treatments for DMD and other muscular dystrophies (Figure 4).

There are pros and cons of transgene-free small molecule-mediated myogenic induction protocols. In the transgene-mediated induction protocols, integration of the transgene in the host genome may lead to risk for insertional mutagenesis. To circumvent this issue, there is an obvious advantage for transgene-free induction protocols. Some key molecules such as Wnt, FGF, and BMP have used signaling pathways to induce myogenic differentiation of ES/iPSCs. However, these molecules are also involved in induction of other types of cell lineages, which makes it difficult for ES/iPSCs to induce pure myogenic cell populations in vitro. By contrast, transgene-mediated myogenic induction is able to dictate desired specific cell lineages. In any case, it is necessary to intensively investigate these myogenic induction protocols for the efficient and safe stem cell therapy for patients.

For skeletal muscle diseases, patient-derived hiPSCs, which possess the ability to differentiate into myogenic progenitor cells followed by myotubes, can be a useful tool for drug screening and personalized medicine in clinical practice. However, there are still limitations for utilizing hiPSC-derived myogenic cells for regenerative medicine. For cell-based transplantation therapies such as a clinical situation, animal-free defined medium is essential for stem cell culture and skeletal muscle cell differentiation. Therefore, such animal-free defined medium needs to be established for optimal myogenic differentiation from hiPSCs. Gene correction in DMD patient iPSCs by TALENs and CRISPR-Cas9 systems are promising therapeutic approaches for stem cell transplantation. However, there are still problems for DNA-editing-mediated stem cell therapy such as safety and efficacy. Since iPSC-derived differentiated myotubes do not proliferate, they are not suited for cell transplantation. Therefore, a proper culture method needs to be established for hiPSCs in order to maintain cells in proliferating the myogenic precursor cell stage in vitro in order to expand cells to large quantities of transplantable cells for DMD and other muscular dystrophies. For other issues, it is essential to establish methods to separate ES/iPSC-derived pure skeletal muscle precursor cells from other cell types for safe stem cell therapy that excludes tumorigenic risks of contamination with undifferentiated cells. In the near future, these obstacles will be taken away for more efficient and safe stem cell therapy for DMD and other muscular dystrophies.

The authors declare that they have no conflicts of interest.

This work was supported by the NIH R01 (1R01AR062142) and NIH R21 (1R21AR070319). The authors thank Conor Burke-Smith and Neeladri Chowdhury for critical reading.

The rest is here:
Skeletal Muscle Cell Induction from Pluripotent Stem Cells

Specific location in the body containing stem cells

Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate.[1] The word 'niche' can be in reference to the in vivo or in vitro stem-cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem-cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to promote either self-renewal or differentiation to form new tissues. Several factors are important to regulate stem-cell characteristics within the niche: cellcell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and the physicochemical nature of the environment including the pH, ionic strength (e.g. Ca2+ concentration) and metabolites, like ATP, are also important.[2] The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.

Scientists are studying the various components of the niche and trying to replicate the in vivo niche conditions in vitro.[2] This is because for regenerative therapies, cell proliferation and differentiation must be controlled in flasks or plates, so that sufficient quantity of the proper cell type are produced prior to being introduced back into the patient for therapy.

Human embryonic stem cells are often grown in fibroblastic growth factor-2 containing, fetal bovine serum supplemented media. They are grown on a feeder layer of cells, which is believed to be supportive in maintaining the pluripotent characteristics of embryonic stem cells. However, even these conditions may not truly mimic in vivo niche conditions.

Adult stem cells remain in an undifferentiated state throughout adult life. However, when they are cultured in vitro, they often undergo an 'aging' process in which their morphology is changed and their proliferative capacity is decreased. It is believed that correct culturing conditions of adult stem cells needs to be improved so that adult stem cells can maintain their stemness over time.[citation needed]

A Nature Insight review defines niche as follows:

"Stem-cell populations are established in 'niches' specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics ... The simple location of stem cells is not sufficient to define a niche. The niche must have both anatomic and functional dimensions."[3]

Though the concept of stem cell niche was prevailing in vertebrates, the first characterization of stem cell niche in vivo was worked out in Drosophila germinal development.

By continuous intravital imaging in mice, researchers were able to explore the structure of the stem cell niche and to obtain the fate of individual stem cells (SCs) and their progeny over time in vivo. In particular in intestinal crypt,[4] two distinct groups of SCs have been identified: the "border stem cells" located in the upper part of the niche at the interface with transit amplifying cells (TAs), and "central stem cells" located at the crypt base. The proliferative potential of the two groups was unequal and correlated with the cells' location (central or border). It was also shown that the two SC compartments acted in accord to maintain a constant cell population and a steady cellular turnover. A similar dependence of self-renewal potential on proximity to the niche border was reported in the context of hair follicle, in an in vivo live-imaging study.[5]

This bi-compartmental structure of stem cell niche has been mathematically modeled to obtain the optimal architecture that leads to the maximum delay in double-hit mutant production.[6] They found that the bi-compartmental SC architecture minimizes the rate of two-hit mutant production compared to the single SC compartment model. Moreover, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs with a large proliferation rate of border stem cells along with a small, but non-zero, proliferation rate of central stem cells.[citation needed]

Stem cell niches harboring continuously dividing cells, such as those located at the base of the intestinal gland, are maintained at small population size. This presents a challenge to the maintenance of multicellular tissues, as small populations of asexually dividing individuals will accumulate deleterious mutations through genetic drift and succumb to mutational meltdown.[7] Mathematical modeling of the intestinal gland reveals that the small population size within the stem cell niche minimizes the probability of carcinogenesis occurring anywhere, at the expense of gradually accumulated deleterious mutations throughout organismal lifetimea process that contributes to tissue degradation and aging.[8] Therefore, the population size of the stem cell niche represents an evolutionary trade-off between the probability of cancer formation and the rate of aging.

Germline stem cells (GSCs) are found in organisms that continuously produce sperm and eggs until they are sterile. These specialized stem cells reside in the GSC niche, the initial site for gamete production, which is composed of the GSCs, somatic stem cells, and other somatic cells. In particular, the GSC niche is well studied in the genetic model organism Drosophila melanogaster and has provided an extensive understanding of the molecular basis of stem cell regulation.[citation needed]

In Drosophila melanogaster, the GSC niche resides in the anterior-most region of each ovariole, known as the germarium. The GSC niche consists of necessary somatic cells-terminal filament cells, cap cells, escort cells, and other stem cells which function to maintain the GSCs.[9] The GSC niche holds on average 23 GSCs, which are directly attached to somatic cap cells and Escort stem cells, which send maintenance signals directly to the GSCs.[10] GSCs are easily identified through histological staining against vasa protein (to identify germ cells) and 1B1 protein (to outline cell structures and a germline specific fusome structure). Their physical attachment to the cap cells is necessary for their maintenance and activity.[10] A GSC will divide asymmetrically to produce one daughter cystoblast, which then undergoes 4 rounds of incomplete mitosis as it progresses down the ovariole (through the process of oogenesis) eventually emerging as a mature egg chamber; the fusome found in the GSCs functions in cyst formation and may regulate asymmetrical cell divisions of the GSCs.[11] Because of the abundant genetic tools available for use in Drosophila melanogaster and the ease of detecting GSCs through histological stainings, researchers have uncovered several molecular pathways controlling GSC maintenance and activity.[12] [13]

The Bone Morphogenetic Protein (BMP) ligands Decapentaplegic (Dpp) and Glass-bottom-boat (Gbb) ligand are directly signalled to the GSCs, and are essential for GSC maintenance and self-renewal.[14] BMP signalling in the niche functions to directly repress expression of Bag-of-marbles (Bam) in GSCs, which is up-regulated in developing cystoblast cells.[15] Loss of function of dpp in the niche results in de-repression of Bam in GSCs, resulting in rapid differentiation of the GSCs.[10] Along with BMP signalling, cap cells also signal other molecules to GSCs: Yb and Piwi. Both of these molecules are required non-autonomously to the GSCs for proliferation-piwi is also required autonomously in the GSCs for proliferation.[16] In the germarium, BMP signaling has a short-range effect, therefore the physical attachment of GSCs to cap cells is important for maintenance and activity.[citation needed]

The GSCs are physically attached to the cap cells by Drosophila E-cadherin (DE-cadherin) adherens junctions and if this physical attachment is lost GSCs will differentiate and lose their identity as a stem cell.[10] The gene encoding DE-cadherin, shotgun (shg), and a gene encoding Beta-catenin ortholog, armadillo, control this physical attachment.[17] A GTPase molecule, rab11, is involved in cell trafficking of DE-cadherins. Knocking out rab11 in GSCs results in detachment of GSCs from the cap cells and premature differentiation of GSCs.[18] Additionally, zero population growth (zpg), encoding a germline-specific gap junction is required for germ cell differentiation.[19]

Both diet and insulin-like signaling directly control GSC proliferation in Drosophila melanogaster. Increasing levels of Drosophila insulin-like peptide (DILP) through diet results in increased GSC proliferation.[20] Up-regulation of DILPs in aged GSCs and their niche results in increased maintenance and proliferation.[21] It has also been shown that DILPs regulate cap cell quantities and regulate the physical attachment of GSCs to cap cells.[21]

There are two possible mechanisms for stem cell renewal, symmetrical GSC division or de-differentiation of cystoblasts. Normally, GSCs will divide asymmetrically to produce one daughter cystoblast, but it has been proposed that symmetrical division could result in the two daughter cells remaining GSCs.[22][23] If GSCs are ablated to create an empty niche and the cap cells are still present and sending maintenance signals, differentiated cystoblasts can be recruited to the niche and de-differentiate into functional GSCs.[24]

As the Drosophila female ages, the stem cell niche undergoes age-dependent loss of GSC presence and activity. These losses are thought to be caused in part by degradation of the important signaling factors from the niche that maintains GSCs and their activity. Progressive decline in GSC activity contributes to the observed reduction in fecundity of Drosophila melanogaster at old age; this decline in GSC activity can be partially attributed to a reduction of signaling pathway activity in the GSC niche.[25][26] It has been found that there is a reduction in Dpp and Gbb signaling through aging. In addition to a reduction in niche signaling pathway activity, GSCs age cell-autonomously. In addition to studying the decline of signals coming from the niche, GSCs age intrinsically; there is age-dependent reduction of adhesion of GSCs to the cap cells and there is accumulation of Reactive Oxygen species (ROS) resulting in cellular damage which contributes to GSC aging. There is an observed reduction in the number of cap cells and the physical attachment of GSCs to cap cells through aging. Shg is expressed at significantly lower levels in an old GSC niche in comparison to a young one.[26]

Males of Drosophila melanogaster each have two testes long, tubular, coiled structures and at the anterior most tip of each lies the GSC niche. The testis GSC niche is built around a population of non-mitotic hub cells (a.k.a. niche cells), to which two populations of stem cells adhere: the GSCs and the somatic stem cells (SSCs, a.k.a. somatic cyst stem cells/cyst stem cells). Each GSC is enclosed by a pair of SSCs, though each stem cell type is still in contact with the hub cells. In this way, the stem cell niche consists of these three cell types, as not only do the hub cells regulate GSC and SSC behaviour, but the stem cells also regulate the activity of each other. The Drosophila testis GSC niche has proven a valuable model system for examining a wide range of cellular processes and signalling pathways.[27]

The process of spermatogenesis begins when the GSCs divide asymmetrically, producing a GSC that maintains hub contact, and a gonialblast that exits the niche. The SSCs divide with their GSC partner, and their non-mitotic progeny, the somatic cyst cells (SCCs, a.k.a. cyst cells) will enclose the gonialblast. The gonialblast then undergoes four rounds of synchronous, transit-amplifying divisions with incomplete cytokinesis to produce a sixteen-cell spermatogonial cyst. This spermatogonial cyst then differentiates and grows into a spermatocyte, which will eventually undergo meiosis and produce sperm.[27]

The two main molecular signalling pathways regulating stem cell behaviour in the testis GSC niche are the Jak-STAT and BMP signalling pathways. Jak-STAT signalling originates in the hub cells, where the ligand Upd is secreted to the GSCs and SSCs.[28][29] This leads to activation of the Drosophila STAT, Stat92E, a transcription factor which effects GSC adhesion to the hub cells,[30] and SSC self-renewal via Zfh-1.[31] Jak-STAT signalling also influences the activation of BMP signalling, via the ligands Dpp and Gbb. These ligands are secreted into the GSCs from the SSCs and hub cells, activate BMP signalling, and suppress the expression of Bam, a differentiation factor.[32] Outside of the niche, gonialblasts no longer receive BMP ligands, and are free to begin their differentiation program. Other important signalling pathways include the MAPK and Hedgehog, which regulate germline enclosure [33] and somatic cell self-renewal,[34] respectively.

The murine GSC niche in males, also called spermatogonial stem cell (SSC) niche, is located in the basal region of seminiferous tubules in the testes. The seminiferous epithelium is composed of sertoli cells that are in contact with the basement membrane of the tubules, which separates the sertoli cells from the interstitial tissue below. This interstitial tissue comprises Leydig cells, macrophages, mesenchymal cells, capillary networks, and nerves.[35]

During development, primordial germ cells migrate into the seminiferous tubules and downward towards the basement membrane whilst remaining attached to the sertoli cells where they will subsequently differentiate into SSCs, also referred to as Asingle spermatogonia.[35][36] These SSCs can either self-renew or commit to differentiating into spermatozoa upon the proliferation of Asingle into Apaired spermatogonia. The 2 cells of Apaired spermatogonia remain attached by intercellular bridges and subsequently divide into Aaligned spermatogonia, which is made up of 416 connected cells. Aaligned spermatogonia then undergo meiosis I to form spermatocytes and meiosis II to form spermatids which will mature into spermatozoa.[37][38] This differentiation occurs along the longitudinal axis of sertoli cells, from the basement membrane to the apical lumen of the seminiferous tubules. However, sertoli cells form tight junctions that separate SSCs and spermatogonia in contact with the basement membrane from the spermatocytes and spermatids to create a basal and an adluminal compartment, whereby differentiating spermatocytes must traverse the tight junctions.[35][39] These tight junctions form the blood testis barrier (BTB) and have been suggested to play a role in isolating differentiated cells in the adluminal compartment from secreted factors by the interstitial tissue and vasculature neighboring the basal compartment.[35]

The basement membrane of the seminiferous tubule is a modified form of extracellular matrix composed of fibronectin, collagens, and laminin.[35] 1- integrin is expressed on the surface of SSCs and is involved in their adhesion to the laminin component of the basement membrane although other adhesion molecules are likely also implicated in the attachment of SSCs to the basement membrane.[40] E cadherin expression on SSCs in mice, unlike in Drosophila, have been shown to be dispensable as the transplantation of cultured SSCs lacking E-cadherin are able to colonize host seminiferous tubules and undergo spermatogenesis.[41] In addition the blood testis barrier provides architectural support and is composed of tight junction components such as occludins, claudins and zonula occludens (ZOs) which show dynamic expression during spermatogenesis.[42] For example, claudin 11 has been shown to be a necessary component of these tight junctions as mice lacking this gene have a defective blood testis barrier and do not produce mature spermatozoa.[40]

GDNF (Glial cell-derived neurotrophic factor) is known to stimulate self-renewal of SSCs and is secreted by the sertoli cells under the influence of gonadotropin FSH. GDNF is a related member of the TGF superfamily of growth factors and when overexpressed in mice, an increase in undifferentiated spermatogonia was observed which led to the formation of germ tumours.[35][40] In corroboration for its role as a renewal factor, heterozygous knockout male mice for GDNF show decreased spermatogenesis that eventually leads to infertility.[40] In addition the supplementation of GDNF has been shown to extend the expansion of mouse SSCs in culture. However, the GDNF receptor c-RET and co-receptor GFRa1 are not solely expressed on the SSCs but also on Apaired and Aaligned, therefore showing that GDNF is a renewal factor for Asingle to Aaligned in general rather than being specific to the Asingle SSC population. FGF2 (Fibroblast growth factor 2), secreted by sertoli cells, has also been shown to influence the renewal of SSCs and undifferentiated spermatogonia in a similar manner to GDNF.[35]

Although sertoli cells appear to play a major role in renewal, it expresses receptors for testosterone that is secreted by Leydig cells whereas germ cells do not contain this receptor- thus alluding to an important role of Leydig cells upstream in mediating renewal. Leydig cells also produce CSF 1 (Colony stimulating factor 1) for which SSCs strongly express the receptor CSF1R.[37] When CSF 1 was added in culture with GDNF and FGF2 no further increase in proliferation was observed, however, the longer the germ cells remained in culture with CSF-1 the greater the SSC density observed when these germ cells were transplanted into host seminiferous tubules. This showed CSF 1 to be a specific renewal factor that tilts the SSCs towards renewal over differentiation, rather than affecting proliferation of SSCs and spermatogonia. GDNF, FGF 2 and CSF 1 have also been shown to influence self-renewal of stem cells in other mammalian tissues.[35]

Plzf (Promyelocytic leukaemia zinc finger) has also been implicated in regulating SSC self-renewal and is expressed by Asingle, Apaired and Aaligned spermatogonia. Plzf directly inhibits the transcription of a receptor, c-kit, in these early spermatogonia. However, its absence in late spermatogonia permits c-kit expression, which is subsequently activated by its ligand SCF (stem cell factor) secreted by sertoli cells, resulting in further differentiation. Also, the addition of BMP4 and Activin-A have shown to reduce self-renewal of SSCs in culture and increase stem cell differentiation, with BMP4 shown to increase the expression of c-kit.[37]

Prolonged spermatogenesis relies on the maintenance of SSCs, however, this maintenance declines with age and leads to infertility. Mice between 12 and 14 months of age show decreased testis weight, reduced spermatogenesis and SSC content. Although stem cells are regarded as having the potential to infinitely replicate in vitro, factors provided by the niche are crucial in vivo. Indeed, serial transplantation of SSCs from male mice of different ages into young mice 3 months of age, whose endogenous spermatogenesis had been ablated, was used to estimate stem cell content given that each stem cell would generate a colony of spermatogenesis.[35][43] The results of this experiment showed that transplanted SSCs could be maintained far longer than their replicative lifespan for their age. In addition, a study also showed that SSCs from young fertile mice could not be maintained nor undergo spermatogenesis when transplanted into testes of old, infertile mice. Together, these results points towards a deterioration of the SSC niche itself with aging rather than the loss of intrinsic factors in the SSC.[43]

Vertebrate hematopoietic stem cells niche in the bone marrow is formed by cells subendosteal osteoblasts, sinusoidal endothelial cells and bone marrow stromal (also sometimes called reticular) cells which includes a mix of fibroblastoid, monocytic and adipocytic cells (which comprise marrow adipose tissue).[1]

The hair follicle stem cell niche is one of the more closely studied niches thanks to its relative accessibility and role in important diseases such as melanoma. The bulge area at the junction of arrector pili muscle to the hair follicle sheath has been shown to host the skin stem cells which can contribute to all epithelial skin layers. There cells are maintained by signaling in concert with niche cells signals include paracrine (e.g. sonic hedgehog), autocrine and juxtacrine signals.[44] The bulge region of the hair follicle relies on these signals to maintain the stemness of the cells. Fate mapping or cell lineage tracing has shown that Keratin 15 positive stem cells' progeny participate in all epithelial lineages.[45] The follicle undergoes cyclic regeneration in which these stem cells migrate to various regions and differentiate into the appropriate epithelial cell type. Some important signals in the hair follicle stem cell niche produced by the mesenchymal dermal papilla or the bulge include BMP, TGF- and Fibroblast growth factor (FGF) ligands and Wnt inhibitors.[46] While, Wnt signaling pathways and -catenin are important for stem cell maintenance,[47] over-expression of -catenin in hair follicles induces improper hair growth. Therefore, these signals such as Wnt inhibitors produced by surrounding cells are important to maintain and facilitate the stem cell niche.[48]

Intestinal organoids have been used to study intestinal stem cell niches. An intestinal organoid culture can be used to indirectly assess the effect of the manipulation on the stem cells through assessing the organoid's survival and growth. Research using intestinal organoids have demonstrated that the survival of intestinal stem cells is improved by the presence of neurons and fibroblasts,[49] and through the administration of IL-22.[50]

Cardiovascular stem cell niches can be found within the right ventricular free wall, atria and outflow tracks of the heart. They are composed of Isl1+/Flk1+ cardiac progenitor cells (CPCs) that are localized into discrete clusters within a ColIV and laminin extracellular matrix (ECM). ColI and fibronectin are predominantly found outside the CPC clusters within the myocardium. Immunohistochemical staining has been used to demonstrate that differentiating CPCs, which migrate away from the progenitor clusters and into the ColI and fibronectin ECM surrounding the niche, down-regulate Isl1 while up-regulating mature cardiac markers such as troponin C.[51] There is a current controversy over the role of Isl1+ cells in the cardiovascular system. While major publications have identified these cells as CPC's and have found a very large number in the murine and human heart, recent publications have found very few Isl1+ cells in the murine fetal heart and attribute their localization to the sinoatrial node,[52] which is known as an area that contributes to heart pacemaking. The role of these cells and their niche are under intense research and debate.[citation needed]

Neural stem cell niches are divided in two: the Subependymal zone (SEZ) and the Subgranular zone (SGZ).

The SEZ is a thin area beneath the ependymal cell layer that contains three types of neural stem cells: infrequently dividing neural stem cells (NSCs), rapidly dividing transit amplifying precursors (TaPs) and neuroblasts (NBs). The SEZ extracellular matrix (ECM) has significant differences in composition compared to surrounding tissues. Recently, it was described that progenitor cells, NSCs, TaPs and NBs were attached to ECM structures called Fractones.[53] These structures are rich in laminin, collagen and heparan sulfate proteoglycans.[54] Other ECM molecules, such as tenascin-C, MMPs and different proteoglycans are also implicated in the neural stem cell niche.[55]

Cancer tissue is morphologically heterogenous, not only due to the variety of cell types present, endothelial, fibroblast and various immune cells, but cancer cells themselves are not a homogenous population either.[citation needed]

In accordance with the hierarchy model of tumours, the cancer stem cells (CSC) are maintained by biochemical and physical contextual signals emanating from the microenvironment, called the cancer stem cell niche.[56] The CSC niche is very similar to normal stem cells niche (embryonic stem cell (ESC), Adult Stem Cell ASC) in function (maintaining of self-renewal, undifferentiated state and ability to differentiate) and in signalling pathways (Activin/Noda, Akt/PTEN, JAK/STAT, PI3-K, TGF-, Wnt and BMP).[57] It is hypothesized that CSCs arise form aberrant signalling of the microenvironment and participates not only in providing survival signals to CSCs but also in metastasis by induction of epithelial-mesenchymal transition (EMT).[citation needed]

Hypoxic condition in stem cell niches (ESC, ASC or CSC) is necessary for maintaining stem cells in an undifferentiated state and also for minimizing DNA damage via oxidation. The maintaining of the hypoxic state is under control of Hypoxia-Inducible transcription Factors (HIFs).[58] HIFs contribute to tumour progression, cell survival and metastasis by regulation of target genes as VEGF, GLUT-1, ADAM-1, Oct4 and Notch.[57]

Hypoxia plays an important role in the regulation of cancer stem cell niches and EMT through the promotion of HIFs.[59] These HIFs help maintain cancer stem cell niches by regulating important stemness genes such as Oct4, Nanog, SOX2, Klf4, and cMyc.[60][61] HIFs also regulate important tumor suppressor genes such as p53 and genes that promote metastasis.[62][63] Although HIFs increase the survival of cells by decreasing the effects of oxidative stress, they have also been shown to decrease factors such as RAD51 and H2AX that maintain genomic stability.[64] In the hypoxic condition there is an increase of intracellular Reactive Oxygen Species (ROS) which also promote CSCs survival via stress response.[65][66] ROS stabilizes HIF-1 which promotes the Met proto-oncogene, which drives metastasis or motogenic escape in melanoma cells.[67] All of these factors contribute to a cancer stem cell phenotype which is why it is often referred to as a hypoxic stem cell niche. Hypoxic environments are often found in tumors where the cells are dividing faster that angiogenesis can occur. It is important to study hypoxia as an aspect of cancer because hypoxic environments have been shown to be resistant to radiation therapy.[68] Radiation has been shown to increase the amounts of HIF-1.[69] EMT induction by hypoxia though interactions between HIF-1 and ROS is crucial for metastasis in cancers such as melanoma. It has been found that many genes associated with melanoma are regulated by hypoxia such as MXI1, FN1, and NME1.[70]

Epithelialmesenchymal transition is a morphogenetic process, normally occurs in embryogenesis that is "hijacked" by cancer stem cells by detaching from their primary place and migrating to another one. The dissemination is followed by reverse transition so-called Epithelial-Mesenchymal Transition (EMT). This process is regulated by CSCs microenvironment via the same signalling pathways as in embryogenesis using the growth factors (TGF-, PDGF, EGF), cytokine IL-8 and extracellular matrix components. These growth factors' interactions through intracellular signal transducers like -catenin has been shown to induce metastatic potential.[71][72] A characteristic of EMT is loss of the epithelial markers (E-cadherin, cytokeratins, claudin, occluding, desmoglein, desmocolin) and gain of mesenchymal markers (N-cadherin, vimentin, fibronectin).[73]

There is also certain degree of similarity in homing-mobilization of normal stem cells and metastasis-invasion of cancer stem cells. There is an important role of Matrix MetalloProteinases (MMP), the principal extracellular matrix degrading enzymes, thus for example matrix metalloproteinase-2 and 9 are induced to expression and secretion by stromal cells during metastasis of colon cancer via direct contact or paracrine regulation. The next sharing molecule is Stromal cell-Derived Factor-1 (SDF-1).[73][74]

The EMT and cancer progression can be triggered also by chronic inflammation. The main roles have molecules (IL-6, IL-8, TNF-, NFB, TGF-, HIF-1) which can regulate both processes through regulation of downstream signalling that overlapping between EMT and inflammation.[57] The downstream pathways involving in regulation of CSCs are Wnt, SHH, Notch, TGF-, RTKs-EGF, FGF, IGF, HGF.

NFB regulates the EMT, migration and invasion of CSCs through Slug, Snail and Twist. The activation of NFB leads to increase not only in production of IL-6, TNF- and SDF-1 but also in delivery of growth factors.

The source of the cytokine production are lymphocytes (TNF-), Mesenchymal Stem Cells (SDF-1, IL-6, IL8).

Interleukin 6 mediates activation of STAT3. The high level of STAT3 was described in isolated CSCs from liver, bone, cervical and brain cancer. The inhibition of STAT3 results in dramatic reduction in their formation. Generally IL-6 contributes a survival advantage to local stem cells and thus facilitates tumorigenesis.[57]

SDF-1 secreted from Mesenchymal Stem Cells (MSCs) has important role in homing and maintenance of Hematopoietic Stem Cell (HSC) in bone marrow niche but also in homing and dissemination of CSC.[74]

Hypoxia is a main stimulant for angiogenesis, with HIF-1 being the primary mediator. Angiogenesis induced by hypoxic conditions is called an "Angiogenic switch". HIF-1 promotes expression of several angiogenic factors: Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), Placenta-Like Growth Factor (PLGF), Platelet-Derived Growth Factor (PDGF) and Epidermal Growth Factor. But there is evidence that the expression of angiogenic agens by cancer cells can also be HIF-1 independent. It seems that there is an important role of Ras protein, and that intracellular levels of calcium regulate the expression of angiogenic genes in response to hypoxia.[73]

The angiogenic switch downregulates angiogenesis suppressor proteins, such as thrombospondin, angiostatin, endostatin and tumstatin. Angiogenesis is necessary for the primary tumour growth.[citation needed]

During injury, support cells are able to activate a program for repair, recapitulating aspects of development in the area of damage. These areas become permissive for stem cell renewal, migration and differentiation. For instance in the CNS, injury is able to activate a developmental program in astrocytes that allow them to express molecules that support stem cells such as chemokines i.e. SDF-1[75] and morphogens such as sonic hedgehog.[76]

It is evident that biophysio-chemical characteristics of ECM such as composition, shape, topography, stiffness, and mechanical strength can control the stem cell behavior. These ECM factors are equally important when stem cells are grown in vitro. Given a choice between niche cell-stem cell interaction and ECM-stem cell interaction, mimicking ECM is preferred as that can be precisely controlled by scaffold fabrication techniques, processing parameters or post-fabrication modifications. In order to mimic, it is essential to understand natural properties of ECM and their role in stem cell fate processes. Various studies involving different types of scaffolds that regulate stem cells fate by mimicking these ECM properties have been done.[2])

[77]

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MALVERN, Pa., Nov. 21, 2022 (GLOBE NEWSWIRE) -- Neuronetics, Inc. (NASDAQ:STIM), a commercial stage medical technology company focused on designing, developing, and marketing products that improve the quality of life for patients who suffer from neurohealth disorders, today announced that Keith Sullivan, President and Chief Executive Officer, and Steve Furlong, Senior Vice President, Chief Financial Officer, and Treasurer, will participate in the Piper Sandler 34th Annual Healthcare Conference on Thursday, December 1, 2022. The Company is scheduled to present at the conference at 9:30 am Eastern Time the same day via webcast.A live audio webcast of the conference presentation will be available online at the investor relations page of the Company’s website at ir.neuronetics.com. A replay of the webcast will be archived on the website for approximately 90 days.About NeuroneticsNeuronetics, Inc. believes that mental health is as important as physical health. As a global leader in neuroscience, Neuronetics is redefining patient and physician expectations with its NeuroStar Advanced Therapy for Mental Health. NeuroStar is a non-drug, noninvasive treatment that can improve the quality of life for people suffering from neurohealth conditions when traditional medication hasn’t helped. NeuroStar is FDA-cleared for adults with major depressive disorder (MDD), as an adjunct for adults with obsessive-compulsive disorder (OCD), and to decrease anxiety symptoms in adult patients with MDD that may exhibit comorbid anxiety symptoms (anxious depression). NeuroStar Advanced Therapy is the leading transcranial magnetic stimulation (TMS) treatment for MDD in adults with over 4.8 million treatments delivered. NeuroStar is backed by the largest clinical data set of any TMS system for depression, including the world’s largest depression Outcomes Registry. Neuronetics is committed to transforming lives by offering an exceptional treatment that produces extraordinary results. For safety and prescribing information, www.neurostar.com.Investor Contact:Mark KlausnerWestwicke Partners443-213-0501ir@neuronetics.comMedia Contact:EvolveMKD646.517.4220NeuroStar@evolvemkd.com

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THE WOODLANDS, Texas, Nov. 11, 2022 (GLOBE NEWSWIRE) -- Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX) today announced its participation in the 13th Annual Jefferies London Healthcare Conference, taking place November 15-17, 2022.

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Lexicon Pharmaceuticals to Participate in the 13th Annual Jefferies London Healthcare Conference