In many ways, the human body is like any other machine in that it requires constant refueling and maintenance to keep functioning. Much of this happens without our intervention beyond us selecting what to eat that day. There are however times when due to an accident, physical illness or aging the automatic repair mechanisms of our body become overwhelmed, fail to do their task correctly, or outright fall short in repairing damage.

Most of us know that lizards can regrow tails, some starfish regenerate into as many new starfish as the pieces which they were chopped into, and axolotl can regenerate limbs and even parts of their brain. Yet humans too have an amazing regenerating ability, although for us it is mostly contained within the liver, which can regenerate even when three-quarters are removed.

In the field of regenerative medicine, the goal is to either induce regeneration in damaged tissues, or to replace damaged organs and tissues with externally grown ones, using the patients own genetic material. This could offer us a future in which replacement organs are always available at demand, and many types of injuries are no longer permanent, including paralysis.

Our level of understanding of human physiology and that of animals in general has massively expanded since the beginning of the 20th century when technology allowed us to examine the microscopic world in more detail than ever before. Although empirical medical science saw its beginnings as early as the Sumerian civilization of the 3rd millennium BCE, our generalized understanding of the processes and components that underlie the bodys functioning are significantly more recent.

DNA was first isolated in 1869 by Friedrich Miescher, but its structure was not described until 1953. This discovery laid the foundations for the field of molecular biology, which seeks to understand the molecular basis for biological activity. In a sense this moment can be seen as transformative as for example the transition from classical mechanics to quantum mechanics, in that it changed the focus from macroscopic observations to a more fundamental understanding of these observations.

This allowed us to massively increase our understanding of how exactly the body responds to damage, and the molecular basis for regenerative processes, as well as why humans are normally not able to regrow damaged limbs. Eventually in 1999 the term regenerative medicine was coined by William A. Haseltine, who wrote an article in 2001 on what he envisions the term to include. This would be the addressing of not only injuries and trauma from accidents and disease, but also aging-related conditions, which would address the looming demographic crisis as the average age of the worlds populations keeps increasing.

The state of the art in regenerative medicine back in 2015 was covered by Angelo S. Mao et al. (2015). This covers regenerative methods involving either externally grown tissues and organs, or the stimulating of innate regenerative capabilities. Their paper includes the biomedical discipline of tissue engineering due to the broad overlap with the field of regenerative medicine. Despite the very significant time and monetary requirement to bring a regenerative medicine product to market, Mao et al. list the FDA-approved products at that time:

While these were not miracle products by any stretch of the imagination, they do prove the effectiveness of these approaches, displaying similar or better effectiveness as existing products. While getting cells to the affected area where they can induce repair is part of the strategy, another essential part involves the extracellular matrix (ECM). These are essential structures of many tissues and organs in the body which provide not only support, but also play a role in growth and regeneration.

ECM is however non-cellular, and as such is seen as a medical device. They play a role in e.g. the healing of skin to prevent scar tissue formation, but also in the scaffolding of that other tantalizing aspect of regenerative medicine: growing entire replacement organs and body parts in- or outside of the patients body using their own cells. As an example, Mase Jr, et al. (2010) report on a 19-year old US Marine who had part of his right thigh muscle destroyed by an explosion. Four months after an ECM extracted from porcine (pig) intestinal submucossa was implanted in the area, gradual regrowth of muscle tissue was detected.

An important research area here is the development of synthetic ECM-like scaffolding, as this would make the process faster, easier and more versatile. Synthetic scaffolding makes the process of growing larger structures in vitro significantly easier as well, which is what is required to enable growing organs such as kidneys, hearts and so on. These organs would then ideally be grown from induced pluropotent stem cells (iPS), which are a patients own cells that are reverted back to an earlier state of specialization.

It should come as little surprise that as a field which brings together virtually every field that touches upon (human) biology in some fashion, regenerative medicine is not an easy one. While its one thing to study a working system, its a whole different level to get one to grow from scratch. This is why as great as it would be to have an essentially infinite supply of replacement organs by simply growing new ones from iPS cells, the complexity of a functional organ makes this currently beyond our reach.

Essentially the rule is that the less complicated the organ or tissue is, the easier it is to grow it in vitro. Ideally it would just consist out of a single type of cell, and happy develop in some growth medium without the need for an ECM. Attractive targets here are for example the cornea, where the number of people on a waiting list for a corneal transplant outnumber donor corneas significantly.

In a review by Mobaraki et al. (2019), the numerous currently approved corneal replacements as well as new methods being studied are considered. Even though artificial corneas have been in use for years, they suffer from a variety of issues, including biocompatibility issues and others that prevent long-term function. Use of donor corneas comes with shortages as the primary concern. Current regenerative research focuses on the stem cells found in the limbus zone (limbal stem cells, LSC). These seem promising for repairing ocular surface defects, which has been studied since 1977.

LSCs play a role in the regular regenerative abilities of the cornea, and provide a starting point for either growing a replacement cornea, or to repair a damaged cornea, along with the addition of an ECM as necessary. This can be done in combination with the inhibiting of the local immune response, which promotes natural wound healing. Even so, there is still a lot more research that needs to be performed before viable treatments for either repairing the cornea in situ, or growing a replacement in vitro can be approved the FDA or national equivalent.

A similar scenario can be seen with the development of artificial skin, where fortunately due to the large availability of skin on a patients body grafts (autografts) are usually possible. Even so, the application of engineered skin substitutes (ESS) would seem to be superior. This approach does not require the removal of skin (epidermis) elsewhere, and limits the amount of scar formation. It involves placing a collagen-based ECM on the wound, which is optionally seeded with keritanocytes (skin precursor cells), which accelerates wound closure.

Here the scaffolding proved to be essential in the regeneration of the skin, as reported by Tzeranis et al. (2015). This supports the evidence from other studies that show the cell adhesion to the ECM to be essential in cell regulation and development. With recent changes, it would seem that both the formation of hair follicles and nerve innervation may be solved problems.

It will likely still be a long time before we can have something like a replacement heart grown from a patients own iPS cells. Recent research has focused mostly on decellularization (leaving only the ECM) of an existing heart, and repopulating it with native cells (e.g. Glvez-Montn et al., 2012). By for example creating a synthetic scaffold and populating it with cells derived from a patients iPS cells, a viable treatment could be devised.

Possibly easier to translate into a standard treatment is the regrowth of nerves in the spinal cord after trauma, with a recent article by lvarez et al, (2021) (press release) covering recent advances in the use of artificial scaffolds that promotes nerve regeneration, reduces scarring and promotes blood vessel formation. This offers hope that one day spinal cord injures may be fully repairable.

If we were to return to the body as a machine comparison, then the human body is less of a car or piece of heavy machinery, and more of a glued-together gadget with complex circuitry and components inside. With this jump in complexity comes the need for a deeper level of understanding, and increasingly more advanced tools so that repairs can be made efficiently and with good outcomes.

Even so, regenerative medicine is already saving the lives of for example burn victims today, and improving the lives of countless others. As further advances in research continue to translate into treatments, we should see a gradual change from youll have to learn to live with that, to a more optimistic give it some time to grow back, as in the case of an injured veteran, or the victim of an accident.

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Regenerative Medicine: The Promise Of Undoing The Ravages Of Time - Hackaday

Skin Stem Cells Comments Off on Regenerative Medicine: The Promise Of Undoing The Ravages Of Time – Hackaday | January 18th, 2022

On January 7, a 57-year-old male patient received a genetically-modified pig heart transplant at the University of Maryland Medical Center (UMMC). The surgery was a world-first and deemed the patients only chance for survival after he was declared unsuitable for a human donor transplant or an artificial heart pump. On January 10, the University of Maryland School of Medicine (UMSOM) published a news release stating that the patient was doing well, and is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits.

Dr. Bartley P. Griffith the surgeon responsible for transplanting the porcine heart into the patient and a professor in transplant surgery at UMSOM said, We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future. Dr. Griffith leads the Cardiac Xenotransplantation Program at UMSOM alongside Dr. Muhammad M. Mohiuddin, professor of surgery at UMSOM.

The operation at the UMMC is an example of xenotransplantation. Xenotransplantation refers to any procedure involving the transplantation, infusion or implantation of cells, tissue or organs from a nonhuman, animal source into a human.

While the surgery was the first-of-its-kind, the concept of xenotransplantation is not novel. Chris Denning, professor of stem cell biology at the University of Nottingham told the UK Science Media Centre, Only in the late 1990s did the technologies become available and have steadily been improved ever since. Various academic and industrial teams have worked in this area for over 20 years, so it is not surprising that this has now been tested.

In the 20th century, non-human primates (NHP) were explored as potentially suitable donors for xenotransplantation due to the genetic similarities between primates and humans. However, concerns such as ethical issues, transmission of infection across species and breeding difficulties halted this research. Consequently, pigs are now considered to be the most appropriate candidate species for xenotransplantation.

"Pigs are considered for several reasons, Denning said. The size and anatomy of the pig heart is roughly the same as a humans, though there are considerable differences:

He added that, despite public perception, it is also relatively easy to keep pigs in a sterile condition.

Despite these advantages, transplanting a porcine heart into a human is considerably more challenging than transplanting a human heart. There are genetic differences between pigs and humans, which can lead to immunological rejection of the organ. Pigs have a gene that produces a molecule called (1,3)galactosyl transferase, which humans do not. This triggers an immediate and aggressive immune response, called hyperacute rejection, said Denning, ultimately causing the body to reject the organ.

The xenotransplantation conducted at UMMC involved a pig that had reportedly received 10 genetic modifications in total. Its unclear at this stage exactly what genes were modified, however the news release from UMSOM states three genes responsible for rapid antibody-mediated rejection of pig organs by humans were knocked out in the pig, and six human genes responsible for immune acceptance were inserted. An additional gene was also knocked out to stop excessive growth of the heart tissue.

Knockout means that an organism has been genetically altered such that it lacks either a single base, a whole gene or several genes. Often, genetic knockouts are utilized in laboratory research to understand how certain genes function, by monitoring changes in the organism when the gene is not expressed.

The porcine heart was provided by Revivicor, a subsidiary of United Therapeutics. You might recall Revivicor as the spin-out company of PPL Therapeutics, the UK-based biotech firm behind the first cloned mammal, Dolly the sheep. In December 2021, Revivicor also supplied New York University Langone Health with a kidney from a genetically-modified pig for an investigational procedure in a deceased human donor. The donor remained on ventilator support, and was closely monitored throughout the procedure and a subsequent observation period, during which the researchers said there were no signs of rejection.

According to the UMSOM news release, it received a $15.7 million research grant to evaluate Revivicor genetically-modified pig UHearts in baboon studies. Mohiuddin and colleagues reportedly applied for permission to conduct human clinical trials of the porcine heart from the US Food and Drug Administration (FDA), but were rejected. Under normal circumstances, IMPs must be evaluated in animal studies prior to human clinical trials this is standard protocol.

However, in the instance of the 57-year-old patient, an exception was made. The FDA granted emergency authorization for the procedure under its expanded access provision. This allows for an individual to access an investigational medicinal product (IMP) outside of clinical trials when there is no alternative therapy option available.

Will it be successful? asked Denning. The fact that the human patient is alive after a few days indicates that immediate hyperacute rejection has been avoided, which is the first hurdle. Only time will tell whether there are issues with chronic rejection, caused by e.g., incompatibility of major and minor histocompatibility complexes. Continuous monitoring will be needed to monitor transmission of potential pathogens, such as porcine endogenous retroviruses or hybrid porcine/human endogenous retroviruses.

Should the patient survive and the xenotransplant prove successful, it will likely raise a lot of questions as to how regulatory bodies move forward. Individual emergency authorization procedures do not generate sufficient data for the widespread implementation of xenotransplantation clinical trials are crucial for demonstrating efficacy.

However, there are logistical hurdles associated with even trialing the procedure. Seventeen people die every day waiting for an organ transplant, according to the Health Resources & Services Administration. There is a severe shortage of organs, and a steep decline in donation has been observed during the COVID-19 global pandemic. While a proposed advantage of xenotransplants is that they could provide on-demand organs, the procedure and its unknowns make it a very high-risk surgery. How does a clinician, or regulatory body, decide that a patient has waited long enough for a human organ that they qualify for inclusion in a trial?

Furthermore, if xenotransplant clinical trials support widespread adoption of xenotransplant procedures, how do we regulate a system whereby organs are widely available? Policies on patient selection and organ allocation currently exist in healthcare systems across the world. Navigating changes to these policies will require global conversations across different regulatory bodies.

Finally, a hurdle that Denning said could be the biggest of them all is: What do the general public think? Is it acceptable to harvest organs from animals? One thing that is for sure, is the outcomes of this [patient] will be watched closely by many, Denning concluded.

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What the World's First Pig to Human Heart Transplant Could Mean for the Future of Transplants - Technology Networks

Cardiac Stem Cells Comments Off on What the World’s First Pig to Human Heart Transplant Could Mean for the Future of Transplants – Technology Networks | January 18th, 2022

Report Oceanpresents a new report onglobalcell therapy processing marketsize, share, growth, industry trends, and forecast 2030, covering various industry elements and growth trends helpful for predicting the markets future.

The global cell therapy processing market was valued at $1,695 million in 2018, and is projected to reach $12,062 million by 2026, registering a CAGR of 27.80% from 2019 to 2026.

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In order to produce a holistic assessment of the market, a variety of factors is considered, including demographics, business cycles, and microeconomic factors specific to the market under study. Global cell therapy processing market report 2021 also contains a comprehensive business analysis of the state of the business, which analyzes innovative ways for business growth and describes critical factors such as prime manufacturers, production value, key regions, and growth rate.

The Centers for Medicare and Medicaid Services report that US healthcare expenditures grew by 4.6% to US$ 3.8 trillion in 2019, or US$ 11,582 per person, and accounted for 17.7% of GDP. Also, the federal government accounted for 29.0% of the total health expenditures, followed by households (28.4%). State and local governments accounted for 16.1% of total health care expenditures, while other private revenues accounted for 7.5%.

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This study aims to define market sizes and forecast the values for different segments and countries in the coming eight years. The study aims to include qualitative and quantitative perspectives about the industry within the regions and countries covered in the report. The report also outlines the significant factors, such as driving factors and challenges, that will determine the markets future growth.

Cell therapy is the administration of living cells to replace a missing cell type or to offer a continuous source of a necessary factor to achieve a truly meaningful therapeutic outcome. There are different forms of cell therapy, ranging from transplantation of cells derived from an individual patient or from another donor. The manufacturing process of cell therapy requires the use of different products such as cell lines and instruments. These cell therapies are used for the treatment of various diseases such as cardiovascular disease and neurological disorders.

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Increase in the incidence of cardiovascular diseases, rise in the demand for chimeric antigen receptor (CAR) T cell therapy, increase in the R&D for the advancement in the research associated with cell therapy, increase in the potential of cell therapies in the treatment of diseases associated with lungs using stem cell therapies, and rise in understanding of the role of stem cells in inducing development of functional lung cells from both embryonic stem cells (ESCs) & induced pluripotent stem (iPS) cells are the key factors that fuel the growth of the cell therapy processing market.

Moreover, increase in a number of clinical studies relating to the development of cell therapy processing, rise in adoption of regenerative drug, introduction of novel technologies for cell therapy processing, increase in government investments for cell-based research, increase in number of GMP-certified production facilities, large number of oncology-oriented cell-based therapy clinical trials, and rise in the development of allogeneic cell therapy are other factors that augment the growth of the market. However, high-costs associated with the cell therapies, and bottlenecks experienced by manufacturers during commercialization of cell therapies are expected to hinder the growth of the market.

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The cell therapy processing market is segmented into offering type, application, and region. By type, the market is categorized into products, services, and software. The application covered in the segment include cardiovascular devices, bone repair, neurological disorders, skeletal muscle repair, cancer, and others. On the basis of region, the market is analyzed across North America (U.S., Canada, and Mexico), Europe (Germany, France, UK, Italy, Spain, and rest of Europe), Asia-Pacific (Japan, China, India, and rest of Asia-Pacific), and LAMEA (Latin America, Middle East, and Africa).

KEY BENEFITS FOR STAKEHOLDERS The study provides an in-depth analysis of the market along with the current trends and future estimations to elucidate the imminent investment pockets. It offers a quantitative analysis from 2018 to 2026, which is expected to enable the stakeholders to capitalize on the prevailing market opportunities. A comprehensive analysis of all the geographical regions is provided to determine the existing opportunities. The profiles and growth strategies of the key players are thoroughly analyzed to understand the competitive outlook of the global market.

LIST OF KEY PLAYERS PROFILED IN THE REPORT Cell Therapies Pty Ltd Invitrx Inc. Lonza Ltd Merck & Co., Inc. (FloDesign Sonics) NantWorks, LLC Neurogeneration, Inc. Novartis AG Plasticell Ltd. Regeneus Ltd StemGenex, Inc.

LIST OF OTHER PLAYERS IN THE VALUE CHAIN (These players are not profiled in the report. The same will be included on request.) Beckman Coulter, Inc. Stemcell Technologies MiltenyiBiotec GmbH

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KEY MARKET SEGMENTSBy Offering Type Products Services Software

By Application Cardiovascular Devices Bone Repair Neurological Disorders Skeletal Muscle Repair Cancer Others

By Region North Americao U.S.o Canadao Mexico Europeo Germanyo Franceo UKo Italyo Spaino Rest of Europe Asia-Pacifico Japano Chinao Indiao Rest of Asia-Pacific LAMEAo Latin Americao Middle Easto Africa

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What are the aspects of this report that relate to regional analysis?

The reports geographical regions include North America, Europe, Asia Pacific, Latin America, the Middle East, and Africa.

The report provides a comprehensive analysis of market trends, including information on usage and consumption at the regional level.

Reports on the market include the growth rates of each region, which includes their countries, over the coming years.

How are the key players in the market assessed?

This report provides a comprehensive analysis of leading competitors in the market.

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This market report shows the projected market size for the cell therapy processing market at the end of the forecast period. The report also examines the historical and current market sizes.

On the basis of various indicators, the charts present the year-over-year growth (%) and compound annual growth rate (CAGR) for the given forecast period.

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The report examines the current state of the industry and the potential growth opportunities in North America, Asia Pacific, Europe, Latin America, and the Middle East, and Africa.

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The report analyzes companies across the globe in detail.

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Cell Therapy Processing Market CAGR of 27.80% Share, Scope, Stake, Trends, Industry Size, Sales & Revenue, Growth, Opportunities and Demand with...

IPS Cell Therapy Comments Off on Cell Therapy Processing Market CAGR of 27.80% Share, Scope, Stake, Trends, Industry Size, Sales & Revenue, Growth, Opportunities and Demand with… | January 3rd, 2022

Definition

A spinal cord injury (SCI) is damage to the tight bundle of cells and nerves that sends and receives signals from the brain to and from the rest of the body. SCI can be caused by direct injury to the spinal cord itself or from damage to the tissue and bones (vertebrae) that surround the spinal cord. This damage can result in temporary or permanent changes in sensation, movement, strength, and body functions below the site of injury. Some injuries that cause little or no cell death may allow for an almost complete recovery while those that occur higher on the spinal cord and are more serious can cause paralysis in most of the body. Motor vehicle accidents and catastrophic falls are the most common causes of SCI in the United States.

An incomplete injury means the spinal cord is still able to trasnmit some messages to and from the brain to the rest of the body. A complete injury means there is no nerve communication and motor function (voluntary movement) below the site where the trauma occurred.

A spinal cord injury can cause one or more symptoms including:

Definition

A spinal cord injury (SCI) is damage to the tight bundle of cells and nerves that sends and receives signals from the brain to and from the rest of the body. SCI can be caused by direct injury to the spinal cord itself or from damage to the tissue and bones (vertebrae) that surround the spinal cord. This damage can result in temporary or permanent changes in sensation, movement, strength, and body functions below the site of injury. Some injuries that cause little or no cell death may allow for an almost complete recovery while those that occur higher on the spinal cord and are more serious can cause paralysis in most of the body. Motor vehicle accidents and catastrophic falls are the most common causes of SCI in the United States.

An incomplete injury means the spinal cord is still able to trasnmit some messages to and from the brain to the rest of the body. A complete injury means there is no nerve communication and motor function (voluntary movement) below the site where the trauma occurred.

A spinal cord injury can cause one or more symptoms including:

Treatment

Immediate treatment at the accident scene includes putting the person on a backboard with a special collar around the neck to prevent further damage to the spinal cord. Treatment at a trauma center may include realigning the spine and surgery to remove any bone fragments or other objects that might press on the spinal column.

Rehabilitative care may include breathing assistance using a machine that produces forced air, treatment for any respiratory or circulatory problems, pain medications, and learning new ways to address bladder and bowel problems. A rehabilitation team will assess the individual's needs and create a rehabilitation program that combines plysical and other therapies with skill-building activities, training, and counseling to aid recovery and provide social and emotional support, as well as to increase independence and quality of life.

Treatment

Immediate treatment at the accident scene includes putting the person on a backboard with a special collar around the neck to prevent further damage to the spinal cord. Treatment at a trauma center may include realigning the spine and surgery to remove any bone fragments or other objects that might press on the spinal column.

Rehabilitative care may include breathing assistance using a machine that produces forced air, treatment for any respiratory or circulatory problems, pain medications, and learning new ways to address bladder and bowel problems. A rehabilitation team will assess the individual's needs and create a rehabilitation program that combines plysical and other therapies with skill-building activities, training, and counseling to aid recovery and provide social and emotional support, as well as to increase independence and quality of life.

Definition

A spinal cord injury (SCI) is damage to the tight bundle of cells and nerves that sends and receives signals from the brain to and from the rest of the body. SCI can be caused by direct injury to the spinal cord itself or from damage to the tissue and bones (vertebrae) that surround the spinal cord. This damage can result in temporary or permanent changes in sensation, movement, strength, and body functions below the site of injury. Some injuries that cause little or no cell death may allow for an almost complete recovery while those that occur higher on the spinal cord and are more serious can cause paralysis in most of the body. Motor vehicle accidents and catastrophic falls are the most common causes of SCI in the United States.

An incomplete injury means the spinal cord is still able to trasnmit some messages to and from the brain to the rest of the body. A complete injury means there is no nerve communication and motor function (voluntary movement) below the site where the trauma occurred.

A spinal cord injury can cause one or more symptoms including:

Treatment

Immediate treatment at the accident scene includes putting the person on a backboard with a special collar around the neck to prevent further damage to the spinal cord. Treatment at a trauma center may include realigning the spine and surgery to remove any bone fragments or other objects that might press on the spinal column.

Rehabilitative care may include breathing assistance using a machine that produces forced air, treatment for any respiratory or circulatory problems, pain medications, and learning new ways to address bladder and bowel problems. A rehabilitation team will assess the individual's needs and create a rehabilitation program that combines plysical and other therapies with skill-building activities, training, and counseling to aid recovery and provide social and emotional support, as well as to increase independence and quality of life.

Prognosis

Retention of movement depends on the type of injury and where it occurs along the spine. Loss of nerve function occurs below the level of injury. An injury higher on the spinal cord can cause paralysis in most of the body and affect all limbs (called tetraplegia or quadriplegia). A lower injury to the spinal cord may cause paralysis affecting the legs and lower body (called paraplegia).

People who survive a spinal cord injury will most likely have medical complications such as chronic pain and bladder and bowel dysfunction, along with an increased susceptibility to respiratory and heart problems. Successful recovery depends upon how well these chronic conditions are handled day to day.

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Prognosis

Retention of movement depends on the type of injury and where it occurs along the spine. Loss of nerve function occurs below the level of injury. An injury higher on the spinal cord can cause paralysis in most of the body and affect all limbs (called tetraplegia or quadriplegia). A lower injury to the spinal cord may cause paralysis affecting the legs and lower body (called paraplegia).

People who survive a spinal cord injury will most likely have medical complications such as chronic pain and bladder and bowel dysfunction, along with an increased susceptibility to respiratory and heart problems. Successful recovery depends upon how well these chronic conditions are handled day to day.

Prognosis

Retention of movement depends on the type of injury and where it occurs along the spine. Loss of nerve function occurs below the level of injury. An injury higher on the spinal cord can cause paralysis in most of the body and affect all limbs (called tetraplegia or quadriplegia). A lower injury to the spinal cord may cause paralysis affecting the legs and lower body (called paraplegia).

People who survive a spinal cord injury will most likely have medical complications such as chronic pain and bladder and bowel dysfunction, along with an increased susceptibility to respiratory and heart problems. Successful recovery depends upon how well these chronic conditions are handled day to day.

Definition

A spinal cord injury (SCI) is damage to the tight bundle of cells and nerves that sends and receives signals from the brain to and from the rest of the body. SCI can be caused by direct injury to the spinal cord itself or from damage to the tissue and bones (vertebrae) that surround the spinal cord. This damage can result in temporary or permanent changes in sensation, movement, strength, and body functions below the site of injury. Some injuries that cause little or no cell death may allow for an almost complete recovery while those that occur higher on the spinal cord and are more serious can cause paralysis in most of the body. Motor vehicle accidents and catastrophic falls are the most common causes of SCI in the United States.

An incomplete injury means the spinal cord is still able to trasnmit some messages to and from the brain to the rest of the body. A complete injury means there is no nerve communication and motor function (voluntary movement) below the site where the trauma occurred.

A spinal cord injury can cause one or more symptoms including:

Treatment

Immediate treatment at the accident scene includes putting the person on a backboard with a special collar around the neck to prevent further damage to the spinal cord. Treatment at a trauma center may include realigning the spine and surgery to remove any bone fragments or other objects that might press on the spinal column.

Rehabilitative care may include breathing assistance using a machine that produces forced air, treatment for any respiratory or circulatory problems, pain medications, and learning new ways to address bladder and bowel problems. A rehabilitation team will assess the individual's needs and create a rehabilitation program that combines plysical and other therapies with skill-building activities, training, and counseling to aid recovery and provide social and emotional support, as well as to increase independence and quality of life.

Prognosis

Retention of movement depends on the type of injury and where it occurs along the spine. Loss of nerve function occurs below the level of injury. An injury higher on the spinal cord can cause paralysis in most of the body and affect all limbs (called tetraplegia or quadriplegia). A lower injury to the spinal cord may cause paralysis affecting the legs and lower body (called paraplegia).

People who survive a spinal cord injury will most likely have medical complications such as chronic pain and bladder and bowel dysfunction, along with an increased susceptibility to respiratory and heart problems. Successful recovery depends upon how well these chronic conditions are handled day to day.

What research is being done?

Scientists at the National Institute of Neurological Disorders and Stroke (NINDS) and those at other institutes at the National Institutes of Health (NIH) conduct and fund research to better understand SCI and how to treat it.

Current research on SCI focuses on advancing our understanding of four key principles of spinal cord repair:

Basic spinal cord function research studies how the normal spinal cord develops, processes sensory information, controls movement, and generates rhythmic patterns (like walking and breathing). Research on injury mechanisms focuses on what causes immediate harm and on the cascade of helpful and harmful bodily reactions that protect from or contribute to damage in the hours and days following a spinal cord injury. Neural engineering strategies also offer ways to restore communication and independence.

Information from the National Library of Medicines MedlinePlusSpinal Cord Injuries

Patient Organizations

Christopher and Dana Reeve Foundation

636 Morris Turnpike

Suite 3A

Short Hills

NJ

Short Hills, NJ 07078

Tel: 973-379-2690; 800-225-0292

Miami Project to Cure Paralysis

1095 NW 14th Terrace

Lois Pope LIFE Center

Miami

FL

Miami, FL 33136

Tel: 305-243-6001; 800-STANDUP (782-6387)

National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR)

Administration for Community Living

330 C St., NW

Washington

DC

Washington, DC 20201

Tel: 202-401-4634; 202-245-7316 (TTY)

National Rehabilitation Information Center (NARIC)

8400 Corporate Drive

Suite 500

Landover

MD

Landover, MD 20785

Tel: 301-459-5900; 800-346-2742; 301-459-5984 (TTY)

National Spinal Cord Injury Statistical Center

1717 6th Avenue South

Birmingham

AL

Birmingham, AL 35232

Paralyzed Veterans of America (PVA)

801 18th Street, NW

Washington

DC

Washington, DC 20006-3517

Tel: 800-424-8200

United Spinal Association

120-34 Queens Boulevard, #320

Kew Gardens

NY

Kew Gardens, NY 11415

Tel: 718-803-3782; 800-962-9629

Publications

Spasticity information sheet compiled by NINDS, the National Institute of Neurological Disorders and Stroke.

Myoclonus fact sheet compiled by the National Institute of Neurological Disorders and Stroke (NINDS).

Patient Organizations

Christopher and Dana Reeve Foundation

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After the therapy performs its function, the materials biodegrade into nutrients for the cells within 12 weeks and then completely disappear from the body without noticeable side effects.This is the first study in which researchers controlled the collective motion of molecules through changes in chemical structure to increase a therapeutics efficacy.

Samuel I. Stupp

Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease, said NorthwesternsSamuel I. Stupp, who led the study. For decades, this has remained a major challenge for scientists because our bodys central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease. We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.

Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of theSimpson Querrey Institute for BioNanotechnology(SQI) and its affiliated research center, theCenter for Regenerative Nanomedicine. He has appointments in theMcCormick School of Engineering,Weinberg College of Arts and SciencesandFeinberg School of Medicine.

According to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with a spinal cord injury in the United States. Life for these patients can be extraordinarily difficult. Less than 3% of people with complete injury ever recover basic physical functions. And approximately 30% are re-hospitalized at least once during any given year after the initial injury, costing millions of dollars in average lifetime health care costs per patient. Life expectancy for people with spinal cord injuries is significantly lower than people without spinal cord injuries and has not improved since the 1980s.

I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients.

Currently, there are no therapeutics that trigger spinal cord regeneration, said Stupp, an expert in regenerative medicine. I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients. Also, new science to address spinal cord injury could have impact on strategies for neurodegenerative diseases and stroke.

A new injectable therapy forms nanofibers with two different bioactive signals (green and orange) that communicate with cells to initiate repair of the injured spinal cord. Illustration by Mark Seniw

The secret behind Stupps new breakthrough therapeutic is tuning the motion of molecules, so they can find and properly engage constantly moving cellular receptors. Injected as a liquid, the therapy immediately gels into a complex network of nanofibers that mimic the extracellular matrix of the spinal cord. By matching the matrixs structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.

Receptors in neurons and other cells constantly move around, Stupp said. The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibers. By making the molecules move, dance or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.

100,000molecules move within the nanofibers

Stupp and his team found that fine-tuning the molecules motion within the nanofiber network to make them more agile resulted in greater therapeutic efficacy in paralyzed mice. They also confirmed that formulations of their therapy with enhanced molecular motion performed better during in vitro tests with human cells, indicating increased bioactivity and cellular signaling.

Given that cells themselves and their receptors are in constant motion, you can imagine that molecules moving more rapidly would encounter these receptors more often, Stupp said. If the molecules are sluggish and not as social, they may never come into contact with the cells.

Once connected to the receptors, the moving molecules trigger two cascading signals, both of which are critical to spinal cord repair. One signal prompts the long tails of neurons in the spinal cord, called axons, to regenerate. Similar to electrical cables, axons send signals between the brain and the rest of the body. Severing or damaging axons can result in the loss of feeling in the body or even paralysis. Repairing axons, on the other hand, increases communication between the body and brain.

Zaida lvarez

The second signal helps neurons survive after injury because it causes other cell types to proliferate, promoting the regrowth of lost blood vessels that feed neurons and critical cells for tissue repair. The therapy also induces myelin to rebuild around axons and reduces glial scarring, which acts as a physical barrier that prevents the spinal cord from healing.

The signals used in the study mimic the natural proteins that are needed to induce the desired biological responses. However, proteins have extremely short half-lives and are expensive to produce, said Zaida lvarez, the studys first author. Our synthetic signals are short, modified peptides that when bonded together by the thousands will survive for weeks to deliver bioactivity. The end result is a therapy that is less expensive to produce and lasts much longer.

A former research assistant professor in Stupps laboratory,lvarez is now a visiting scholar at SQI and a researcher at theInstitute for Bioengineering of Catalonain Spain.

While the new therapy could be used to prevent paralysis after major trauma (automobile accidents, falls, sports accidents and gunshot wounds) as well as from diseases, Stupp believes the underlying discovery that supramolecular motion is a key factor in bioactivity can be applied to other therapies and targets.

The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinsons disease and Alzheimers disease, Stupp said. Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets.

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Whether a deadly disease like cancer and Alzheimers or a lifelong affliction like diabetes, eczema, or arthritis, 2021 has been a year of breakthroughs and advancements.

Beyond COVID-19 and the developments of the mRNA vaccines created to halt the pandemic, medical researchers around the world continued to focus on the long-entrenched problems that have plagued our health for centuries.

Here are some of the top Health stories from 2021:

Routinely polled as one of the most-feared diseases, Alzheimers researchers have hailed several achievements this year.

One fascinating focus has been on prevention, or what contributes to the disease.

A neuroscientist who authored a book called The First Survivors of Alzheimers is not so much focused on drugs as he is focused on brain prevention and is achieving results never before seen in the history of Alzheimers treatment. (Read more)

The findings of a drug that seemed to restore normal cognition in a variety of cases ranging from traumatic brain injury, to noise-related hearing loss, to neurodegenerative disease seem to suggest, its creators write, that age-related cognitive loss may be down to a physiological blockage rather than permanent damage. (Read More)

As seen many times before, sometimes the best new cure is an old drug. Four drugstwo non-steroidal anti-inflammatories, along with two anti-hypertensives, proved effective at reversing Alzheimers disease and neutralizing symptoms in mice suffering from various stages of the illness. (Read More)

As long as theres lifeforms, there will be cancer, but that doesnt mean we cant learn how to treat it, strike at the root cause, and hopefully turn at least some forms of it from one of the major killers to a minor inconvenience.

With 12,000 Britons diagnosed with head and neck cancer every year, the results of a phase III trial that saw complete eradication in some patients, and side-effect-free life extension in others, has the country excited. (Read More)

Discovering an RNA molecule that regulates a key driver in the growth of prostate cancer cells is noteworthy because prostate cancer is one of the most common in men around the world, and because most drugs work for a short period of time before the cancer becomes resistant to it. (Read More)

Despite the gradual awareness of the harmful effects of sugar and bread on the body, chronic diabetes and juvenile diabetes continues to be a major problem in our society.

It turns out that all it takes for this potential cure to rid a patient of a debilitating autoimmune disease is a small piece of adult skin no larger than a housefly. With FDA trials underway, hundreds of thousands of Type-1 diabetics have a chance at a potential cure. (Read More)

Nearly 500 million diabetics around the world need to mildly stab themselves in order to ensure they are in no danger of going into shock. An Australian med-tech company has a new solution. (Read More)

Afflicting a quarter of all Americans, and the leading cause of workplace disability resulting in $303 billion in lost productivity, arthritis took a step towards a cure in 2021.

An alternative to highly addictive painkillers is offering those who undergo knee replacements a large measure of safe relief. Many arthritis patients have knees and hips replaced in the hope of regaining some measure of mobility later in life, but the resulting pain and stiffness can sometimes only be treated with opioids. (Read More)

Osteoarthritis is the most common form, and it affects 8.5 million people. Nasal cells come from a special class of adaptive tissues produced in the brain and spinal cord that can be used to relieve chronic inflammation in the knee and lay the groundwork for a therapeutic treatment that spares patients of surgery and prosthesis. (Read More)

It would seem silly to write a list such as this without addressing the elephant in the room, but as the pandemic petered on through 2021, breakthroughs continued to be made.

One of Americas most favorite medicines was found, unsurprisingly to some doctors, to have as strong an effect as vaccines in some cases at mitigating the severe symptoms of COVID-19. (Read More)

Along with an Israeli nasal spray that prevented infection in 99% of patients, another was found in trials at the University of Oxford which killed 99% of the virus in the nasal passage. (Read More)

Some demonstrations of prosthetic internal organs have shocked the world in 2021, providing a glimpse of a sci-fi future for human anatomy.

A bio-tech implant that allowed a 78-year old blind man to see his family again actually binds with the inside of the eye-socket in a way that had never been done before. (Read More)

The worlds first legit prototype for an artificial kidney was successfully tested when the blood filter and bio reactor components were demonstrated to work together, offering hope to free kidney disease patients from dialysis machines and transplant lists. (Read More)

Ticks, as awful as they are, have their place in the Web of Life. Researchers have identified a soil microbe that eliminates Lyme Disease but essentially nothing else, not even the ticks, opening the door to ecosystem wide treatment against Lyme Disease. (Read More)

Stem cells prepared with the patients own bone marrow were used to repair damaged spinal cords and restore mobility and motor functions in more than half of a Yale scientists trial. (Read More)

An incurable autoimmune disorder that results in progressive motor function loss and neurodegeneration, an MS breakthrough was achieved using the same mRNA vaccines that worked so well originally to stop the COVID pandemic. (Read More)

A monoclonal antibody that reduces the amount of inflammatory molecules that cause a hormonal dysregulation leading to eczema was a treatment generated by this totally surprise finding. (Read More)

Habit Cough the name for a cough without a cause has been cured through a YouTube video relying mostly on the power of suggestion. While this may seem a little sketchy, many people with habit cough have no underlying respiratory condition of any kind, and therefore an ounce of suggestion may beat a cure. (Read More)

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Though there are several skin care treatments available, people should look for the one which is most suitable for their skin and their bank balance (Image: Shutterstock)

If you are looking forward to taking extra care of your skin in the upcoming year, you should be well aware of the best products and treatments available in the market. When it comes to picking a product or a treatment for your face, people are very cautious and they want to go with a brand that has a good reputation in the market and has garnered good reviews. Though there are several skin care treatments available, people should look for the one which is most suitable for their skin and their bank balance. Dr Kiran Sethi Lohia, Integrative Aesthetic and Skin Specialist, who hails from New Delhi in a chat with ETimes, shared some trends that are likely to dominate the beauty industry in 2022.

Stem cells: Stem cells are new to the game, they are added post laser or through micro-needling or even injecting for anti-ageing. In case you have suffered an injury on the face, they are known for wound healing too. Stem cells promote cell turnover, and they also increase collagen production.

Patch-based skincare: We get patches to apply on zits to make them smaller, and soon you will be able to buy and apply patches with tiny microneedles.

Skin boosters: Skin boosters that use injections to hydrate the skin deeply will definitely become a big trend in 2020. As we get older our skin becomes weaker letting out hydration, hence it is difficult to stay hydrated by just drinking water and good skincare. These skin boosters keep our skin supple, elastic, moist, and also prevents aging!

Sculpsure: Sculpsure is the new treatment to lose fat in 2020. The side effect free Sculpsure is approved by the US FDA. It takes 25 minutes per area.

Read all the Latest News, Breaking News and Coronavirus News here.

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Cardiac muscle cells or cardiomyocytes (also known as cardiac myocytes) are the muscle cells (myocytes) that make up the heart muscle. Cardiomyocytes go through a contraction-relaxation cycle that enables cardiac muscles to pump blood throughout the body.

[In this image] Immunostaining of human cardiomyocytes with antibodies for actin (red), myomesin (green), and nuclei (blue).Photo source: https://www.fujifilmcdi.com/products/cardiac-cells/icell-cardiomyocytes

Cardiomyocytes are highly specialized cell types in terms of their structures and functions. Each cardiomyocyte contains myofibrils, unique organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells.

[In this image] Cardiomyocyte geometry and cellular architecture are controlled by micropatterned ECM substrate. Scientists used this technique to study how cells sense and respond to mechanical forces.Photo source: https://diseasebiophysics.seas.harvard.edu/research/mechanotransduction/

The heart is a muscular organ that pumps blood through the blood vessels of the circulatory system. It is composed of individual heart muscle cells (cardiomyocytes) and several other cell types.

[In this figure] The anatomy of the human heart showing 4 heart chambers (left atrium, left ventricle, right atrium, right ventricle) and the blood flow. The myocardium is referred to the cardiac muscle layers building the wall of each chamber.

[In this figure] The thickness of the heart wall (or myocardium) consists of cardiac muscle cells.Photo source: biologydictionary

[In this video] Structure of the human heart.

Cardiovascular disease is a leading cause of death worldwide. Nearly 2,400 Americans die of cardiac causes each day, one death every 37 seconds.

As the chief cell type of the heart, cardiac muscle cells primarily dedicate to the contractile function of the heart and enable the pumping of blood around the body. If anything goes wrong in the heart, it can lead to a catastrophic outcome. A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow ceases to a part of the heart, causing massive cardiomyocyte death in that area. Severe cases can, ultimately, lead to heart failure and death.

[In this figure] The progress of myocardial infarction or heart attack. At time post-infarction:

0-12 hours: Beginning of necrotic coagulation due to the blockage of coronary arteries Cardiomyocytes suffer the lack of oxygen (hypoxia)

12-72 hours: Culmination of necrotic coagulation Neutrophils infiltrate by an inflammatory response.

1-3 weeks: Disintegration of death myocytes and formation of granulation tissue (collagenous fibers, macrophages, and fibroblasts)

> 1 month: Formation of fibrous scar (fewer cells with an abundance of collagenous fibers)

A human heart contains an estimated 23 billion cardiomyocytes. There are several non-myocyte populations in the heart, including endothelial cells, smooth muscle cells, myofibroblasts, epicardial cells, endocardial cells, valve interstitial cells, resident macrophages, and other immune system-related cells, and potentially, adult stem cells (mesenchymal stem cells and cardiac stem cells). These distinct cell pools are not isolated from one another within the heart but interact physically to maintain the function of the whole organ. Overall, cardiomyocytes only account for less than a third of the total cell number in the heart.

[In this image] Immunostaining showing highly vascularized heart muscle.Cardiomyocytes are labeled by the striated pattern of sarcomeric -actinin (green). Capillaries are red and nuclei are blue.Photo source: biocompare.

The three main types of muscle include: Cardiac muscle, Skeletal muscle, and Smooth muscle.

[In this figure] Morphology and comparison of cardiac, skeleton, and smooth muscles.

Note: Involuntary muscles are the muscles that cannot be controlled by will or conscious.

There are two types of cells within the heart: the cardiomyocytes and the cardiac pacemaker cells.

The heart is composed of cardiac muscle cells that have specialized features that relate to their function:

These structural features contribute to the unique functional properties of the cardiac tissue:

Like other animal cells, cardiomyocytes contain all the cell organelles that are essential for normal cell physiology. Moreover, cardiomyocytes have several unique cellular structures that allow them to perform their function effectively. Here are five main characteristics of mature cardiomyocytes: (1) striated; (2) uninucleated; (3) branched; (4) connected by intercalated discs; (5) high mitochondrial content.

[In this figure] Main characteristics of cardiac myocytes.Modified from lumen Anatomy and Physiology I.

Lets get closer to look inside a cardiomyocyte and learn its unique ultrastructure.

All cardiomyocytes and pacemaker cells are linked by cellular bridges. Intercalated discs, which form porous junctions, bring the membranes of adjacent cardiomyocytes very close together. These pores (gap junctions) permit ions, such as sodium, potassium, and calcium, to easily diffuse from cell to cell, establishing a cell-cell communication. This joining is called electric coupling, and it allows the quick transmission of action potentials and the coordinated contraction of the entire heart.

Intercalated discs also function as mechanical anchor points that enable the transmission of contractile force from one cardiomyocyte to another (by desmosomes and adherens junctions). This allows for the heart to work as a single coordinated unit.

[In this figure] Cardiac muscle cells are connected together to coordinate the cardiac contraction. This joining is called electric coupling and is achieved by the presence of irregularly-spaced dark bands between cardiomyocytes. These bands are known as intercalated discs.Photo source: bioninja.

[In this figure] Cardiac myocytes are branched and interconnected from end to end by structures called intercalated disks, visible as dark lines in the light microscope.Photo source: https://doctorlib.info/physiology/medical/49.html

There are 3 main types of junctional complexes within the intercalated discs. They work in different ways to maintain cardiac tissue integrity and cardiomyocyte synchrony.

The term desmosome came from Greek words of bonding (desmo) and body (soma). Desmosomes serve as the anchor points to bring the cardiac muscle fibers together. Desmosomes can withstand mechanical stress, which allows them to hold cells together. Without desmosomes, the cells of the cardiac muscles will fall apart during contraction.

The ability of desmosome to resist mechanical stress comes from its unique 3-D structure. Desmosome is an asymmetrical protein complex bridging between two adjacent cardiomyocytes, with each end residing in the cytoplasm. The intracellular part anchors intermediate filaments in the cytoskeleton to the cell surface. The middle part bridges the intercellular space between two cytoplasmic membranes.

[In this figure] Desmosomes connect intermediate filaments from two adjust cardiomyocytes. This job is accomplished by the formation of a dense protein complex or plaque in the intercalated discs. Major protein players include transmembrane cadherins: desmogleins (Dsgs) and desmocollins (Dscs), cytoplasmic anchors: plakophilins (PKPs) and plakoglobin (PG), and cytoskeleton adaptor: desmoplakin (DP). Cadherins link cells together, and other proteins form a dense complex called plaque.

In addition to desmosomes, adherens junctions (Ajs) are another type of mechanical intercellular junctions in cardiomyocytes. The difference is that adherens junctions link the intercalated disc to the actin cytoskeleton and desmosomes attach to intermediate filaments.

Adherens junctions keep the cardiac muscle cells tightly together as the heart pump. Adherens junctions are also the anchor point where myofibrils are attached, enabling transmission of contractile force from one cell to another.

[In this figure] Adherens junctions link actin cytoskeleton from two adjust cardiomyocytes together.Adherens junctions are constructed from cadherins and catenins. Cadherins (in cardiomyocytes N-Cadherin is the main cadherin) are transmembrane proteins that zip together adjacent cells in a homophilic manner. The transmembrane cadherins form complexes with cytosolic catenins, thereby establishing the connection to the actin cytoskeleton. At the adherens junctions, the opposing membranes become separated by 20nm.

Gap junctions are essential for the chemical and electrical coupling of neighboring cells. Gap junctions work like intercellular channels connecting the cytoplasm of neighboring cells, enabling passive diffusion of various compounds, like metabolites, water, and ions, up to a molecular mass of 1000 Da. Thereby they establish direct communication between adjacent cells.

[In this figure] Neonatal rat cardiac myocytes in cell culture.Cells were immunostained for actinin (green), gap junctions (red), and counterstained with DAPI (blue).Photo source: bioscience

Gap junctions are present in nearly all tissues and cells throughout the entire body. In cardiac muscle, gap junctions ensure proper propagation of the electrical impulse (from pacemaker cells to neighboring cardiomyocytes). This electrical wave triggers sequential and coordinated contraction of the cardiomyocytes as a whole.

[In this figure] A gap junction channel consists of twelve connexin proteins, six of which are contributed by each cell. The six connexin subunits form a hemi-channel in the plasma membrane, which is called a connexon. A connexon docks to another connexon in the intercellular space to create a complete gap junction channel. The intercellular space between adjacent cells at the site of a gap junction is 2-4 nm.

A second feature of cardiomyocytes is the sarcomeres, which are also present in skeletal muscles. The sarcomeres give cardiac muscle their striated appearance and are the repeating sections that make up myofibrils.

[In this image] Freshly isolated heart muscle cells showing intercalated discs (green), sarcomeres (red), and nuclei (blue).Photo source: https://christianz.artstation.com/

Cardiac muscle cells are equipped with bundles of myofibrils that contain myofilaments. These fiber-like structures can occupy 45-60% of the volume of cardiomyocytes. The myofibrils are formed of distinct, repeating units, termed sarcomeres. The sarcomeres, which are composed of thick and thin myofilaments, represent the basic contractile units of a muscle cell and are defined as the region of myofilament structures between two Z-lines (see image below). The distance between Z-lines in human hearts ranges from around 1.6 to 2.2 m.

[In this figure] Labeled diagram of myofibril showing the unit of a sarcomere. A sarcomere is defined as a segment between two neighboring Z-discs.

[In this image] Immunofluorescence image of adult mouse cardiomyocytes showing the Z-lines of the sarcomeres. 3D color projection of alpha-actinin 2 acquired with a confocal microscope.Photo source: Dylan Burnette.

The thick filaments are composed of myosin II. Each myosin contains two ATPase sites on its head. ATPase hydrolyzes ATP and this process is required for actin and myosin cross-bridge formation. These heads bind to actin on the thin filaments. There are about 300 molecules of myosin per thick filament.

The thin filaments are composed of single units of actin known as globular actin (G-actin). Two strands of actin filaments form a helix, which is stabilized by rod-shaped proteins termed tropomyosin. Troponin proteins, which function as regulators, bind to the tropomyosin at regular intervals. Whereas troponin lies in the grooves between the actin filaments, tropomyosin covers the sites on which actin binds to myosin. Their respective actions, therefore, control the binding of myosin to actin and consequently in the contraction and relaxation of cardiac muscles.

To generate muscular contraction, the myosin heads bind to actin filaments, allowing myosin to function as a motor that drives filament sliding. The actin filaments slide past the myosin filaments toward the middle of the sarcomere. This results in the shortening of the sarcomere without any change in filament length.

[In this figure] Sliding-filament model of muscle contraction.

Sarcolemma (also called myolemma) is a specialized cell membrane of cardiomyocytes and skeletal muscle cells. It consists of a lipid bilayer and a thin outer coat of polysaccharide material (glycocalyx) that contacts the basement membrane. The sarcolemma is also part of the intercalated disks as well as the T-tubules of the cardiac muscle.

Basement membrane is an extracellular matrix (ECM) coat that cover individual cardiomyocytes. Its composed of glycoproteins laminin and fibronectin, type IV collagen as well as proteoglycans that contribute to its overall width of about 50nm. Basement membrane provides a scaffold to which the muscle fiber can adhere.

[In this figure] A cross-section of a mouse heart showing the basement membrane (green) wrapping around an individual myocyte.

In cardiomyocytes and skeletal muscle cells, the sarcolemma (i.e. the plasma membrane) forms deep invaginations known as T-tubules (or transverse tubules). These invaginations increase the total surface area and allow depolarization of the membrane to penetrate quickly to the interior of the cell.

Without t-tubules, the wave of calcium ions (Ca2+) takes time to propagate from the periphery of the cell into the center. This time lag will first activate the peripheral sarcomeres and then the deeper sarcomeres, resulting in sub-maximal force production.

The t-tubules make it possible that current is simultaneously relayed to the core of the cell, and trigger near to all sarcomeres simultaneously, resulting in a maximal force output. T-tubules also stay close to sarcoplasmic reticulum (SR) networks, which is the modified endoplasmic reticulum (ER) of calcium storage in myocytes.

[In this figure] T-tubules (transverse tubules) are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. T-tubules permit the rapid transmission of the action potential into the cell and also play an important role in regulating cellular calcium concentration.

Mitochondria are the powerhouse of the cell because they generate most of the cells energy supply of adenosine triphosphate (ATP). It is no doubt that the normal functions of cardiomyocytes require a lot of energy. Effective heart pumping is primarily dependent on oxidative energy production by mitochondria. Cardiomyocytes have a densely packed mitochondrial network, which allows them to produce ATP quickly, making them highly resistant to fatigue.

Different types of mitochondria can be distinguished within cardiomyocytes, and their morphological features are usually defined according to their location: intermyofibrillar mitochondria, subsarcolemmal mitochondria, and perinuclear mitochondria.

[In this figure] Mitochondrial morphology in cardiomyocytes.(Top) The anatomy of a mitochondrion. (Bottom left) Schematic diagram of the location of subsarcolemmal mitochondria (SSM), interfibrillar mitochondria (IFM), and perinuclear mitochondria (PNM). (Bottom right) TEM images of mitochondria in cardiomyocytes.Photo source: researchgate, wiki

Intermyofibrilar Mitochondria are found deeper within the cells and strictly ordered between rows of contractile proteins, apparently isolated from each other by repeated arrays. They play a huge role in producing enough energy for muscle contractions.

[In this figure] Immunofluorescent confocal imaging showing the densely packed mitochondria in cardiomyocytes. (A): Z-line (actinin); (B): Mitochondria; (C): Merge image.Photo source: MDPI

Subsarcolemmal Mitochondria reside beneath the sarcolemma. They collect oxygen from the circulating blood in the arteries and are responsible for providing the energy needed for conserving the integrity of the sarcolemma.

Perinuclear mitochondria are organized in clusters around the nucleus to provide energy for transcription and translation processes.

The cardiac function requires high energy demands; therefore, the adult cardiomyocytes contain numerous mitochondria, which can occupy at least 30% of cell volume. They meet >90% of the energy requirements by oxidative phosphorylation (OXPHOS) in the mitochondria, which requires a huge demand for oxygen consumption.

In humans, at a heart rate of 6070 beats per minute, the oxygen consumption of the myocardium is 20-fold higher than that of skeletal muscle at rest (compared by a normalization per gram of cell mass). In order to meet this high oxygen demand, the capillary density in the heart is 2-8 times higher than that in skeletal muscle (3,0004,000/mm2 compared to 5002,000 capillaries/mm2, respectively). Also, cardiomyocytes maintain a very high level of oxygen extraction (from blood) of 7080% compared with 3040% in skeletal muscle.

[In this image] Myofibrils in cultured cardiomyocytes.Photo source: https://christianz.artstation.com/

Cardiomyocytes go through a contraction-relaxation cycle that enables cardiac muscles to pump blood throughout the body. This is achieved through a process known as excitation-contraction coupling (ECC) that converts action potential (an electric stimulus) into muscle contraction.

[In this figure] Schematic diagram of the process of cardiac excitation-contraction coupling.Key steps in the cardiac excitation-contraction coupling:

Step 1: An action potential is induced by pacemaker cells. It travels along the sarcolemma and down into the T-tubule system to depolarize the cell membrane.

Step 2: Calcium channels in the T-tubules are activated by the action potential and permit calcium entry into the cell.

Step 3: Calcium influx triggers a subsequent release of calcium that is stored in the sarcoplasmic reticulum (SR).

Step 4: Free calcium binds troponin-C (TN-C) that is part of the regulatory complex attached to the thin filaments. Calcium binding moves the troponin complex from the actin binding site. As a result, actin is free to bind myosin. The actin and myosin filaments slide past each other thereby shortening the sarcomere length, thus initiating contraction.

Step 5: At the end of a contraction, calcium entry into the cell slows and calcium is sequestered by the SR by calcium pumps. Lowering the cytosolic calcium concentration releases myosin-actin binding and the initial sarcomere length is restored.

In human beings (and many other animals), cardiomyocytes are the first cells to terminally differentiate, thus making the heart one of the first organs to form in a developing fetus. This makes sense because the function of the circulatory system is so crucial for a growing embryo so that the heart is the top priority.

In the embryo of a mouse, for instance, precursor cells of the cardiac muscles have been shown to start developing about 6 days after fertilization. In human embryos, the heart begins to beat at about 22-23 days, with blood flow beginning in the 4th week. The heart is therefore one of the earliest differentiating and functioning organs.

The heart forms initially in the embryonic disc as a simple paired tube (heart tube formation; week 3) derived from mesoderm. Then, the heart tubes loop and begin segmenting to separate chambers primitive atrium, and primitive ventricle. During this period, the first heartbeat begins.

[In this figure] The timeline of heart development.LA means left atrium; RA means right atrium. For more details, seehttps://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Heart_Development

Here, cardiomyocytes grow into a spongy-like tissue (cardiac jelly), called trabeculation, to build up the thickness of myocardial muscles. Thus, the heart begins to resemble the adult heart in that it has two atria, two ventricles, and the aorta forming a connection with the left ventricle while the pulmonary trunk forms a connection with the right ventricle.

As you can see that our hearts went through a complex developmental process. Inevitably, heart developmental abnormalities could happen (affect 8-10 of every 1000 births in the United States).

Can cardiomyocytes divide? Scientists used to believe that damaged human cardiac muscles cannot regenerate themselves by cell division in adults. In other words, all cardiomyocytes are terminally differentiated. In humans, our cardiomyocytes lose the ability to divide at around 7 days after birth. However, studies have recently shown that myocytes renew at a significantly low rate throughout the life of an individual. For instance, for younger people, about 25 years of age, the annual turnover of cardiomyocytes is about 1 percent. This, however, decreases to about 0.45 percent for older individuals (75 and above). Over the lifespan of an individual, less than 50 percent of these cells are renewed. Comparing to many of the other cells, cardiomyocytes have a very long lifespan. In contrast, small intestine epithelium renews every 2-7 days and hepatocytes (liver cells) renew every 0.5-1 year.

[In this figure] Radiocarbon dating establishes the age of human cardiomyocytes.Scientists used a pretty smart way to estimate the turnover of human heart cells. Generally speaking, the half-life of 14C is too long to date a lifetime of less than a century. However, the dramatic increase in the atmospheric 14C caused by nuclear bomb tests (during the Cool War) in the 1950s and 1960s increased the sensitivity of radiocarbon dating to a temporal resolution of 1-2years.Photo source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837331/

Low turnover of human cardiomyocytes suggests that the regenerative ability of cardiac muscles may be poor (another example is neural cells in the brain). In the event of injuries or myocardial infarction, the injured heart muscles of human beings do not regenerate sufficiently to allow the heart to heal itself. Instead, fibrotic scar tissue forms in the injured site (fibrosis), and the heart functions are compromised, leading to heart failure.

Currently, a number of methods have been studied to repair a broken heart by regenerating cardiomyocytes. These new inventions benefit from the recent advances in biotechnology, especially stem cell biology, regenerative medicine, and tissue engineering. Hopefully, this can bring new therapeutic options to patients with cardiovascular diseases in the near future.

Studies suggested that even in adults, a very small population of progenitor cells reside in the heart and are capable of producing new cardiac myocytes. These cells, known as cardiac stem cells, may not be able to regenerate fast enough to repair a large area of damaged myocardium naturally in humans. However, these cells have shown to be powerful in regenerative capability in other species, like zebrafish.

Scientists believe that once we understand these cardiac progenitors more, we may isolate and expand these cells in quantity, and transplant them to repair damaged heart tissues. For example, we already learned that these cardiac stem cells express cell surface markers like c-Kit (sca-1 in mouse) and aggregate into cardiac spheres.

[In this figure] Multiple different stem cell populations have been described in the adult heart, including c-Kit and Sca-1 cells that were shown to be cardiac progenitors.Photo source: https://dev.biologists.org/content/143/8/1242

Induced pluripotent stem cell (iPSC) technology is a huge revolution in biotechnology. Patients cells (easily obtained from skin biopsy or even urine) can be converted into powerful pluripotent stem cells that have unlimited proliferation capacity and can differentiate any cell type of our body. This eliminates the need to use human embryos for this purpose. Furthermore, these cells are autologous, meaning they wont be rejected by the immune system after transplantation.

Using iPSC technology, researchers have been able to obtain unlimited amounts of functional cardiomyocytes for cell transplantation. Basically, they control the Wnt pathway to convert iPSCs to mesodermal progenitor cells, then play with several growth factors to direct the cardiac vascular progenitors (Flk1+). Following glucose starvation, pure cardiomyocytes can be selected. You can even see these cells beating in the dish.

Therapeutic implantation of iPSC-derived cardiomyocytes progresses pretty fast. We already witnessed successful cell engraftment and cardiac repairing in non-human primates and human patients.

[In this video] Heart cells derived from iPSC stem cells beating in a cell culture dish.

Cardiac fibroblasts make up a significant portion of the total cardiac cells. In the injured heart, these fibroblasts will become active myofibroblasts and form scar tissue. Myofibroblasts survive very well and have ability to coupled with neighboring cells; therefore, myofibroblasts have been shown to be particularly ideal for direct reprogramming to convert them into cells that resemble cardiomyocytes.

Over the past decade, a number of studies have been successfully conducted, reprogramming fibroblasts into cardiomyocyte-like cells. In principle, scientists expressed transcription factors (i.e., Gata4, Mef2c, and Tbx5) that play critical roles in cardiomyocyte differentiation to force the conversion of fibroblasts. Ideally, these genes can be delivered directly to the injured heart via viruses or nanoparticles to perform in situ reprogramming.

Scientists also put their efforts into how to stimulate mature cardiomyocytes to proliferate again (Mature cardiomyocytes typically do not proliferate.) This strategy, called cell cycle re-entry, recently gained success by screening many cell-cycle regulators. Scientists found a combination of cyclin-dependent kinases (CDK) and cyclins, or regulators of the Hippo-YAP signaling pathway can do so. These findings reveal the possibility to efficiently unlock the proliferative potential in cells that had terminally exited the cell cycle.

[In this figure] Potential cardiac regenerative therapies.Photo source: https://www.nature.com/articles/s41536-017-0024-1

Cardiomyocytes can be observed by staining of histological sections of the heart. Since the heart is a 3-D organ, make sure you cut the heart at the right angle.

[In this figure] (Left) A longitudinal section through both ventricles should be made from the base to the apex of the heart. (Right) A cross-section of the heart. H&E staining.(Ao: aorta, At: atrium, Lv: left ventricle, Rv: right ventricle)

Common histological staining for heart tissues includes Hematoxylin and eosin (H&E) and Massons trichrome staining.

[In this figure] A cross section of mouse heart stained by Massons trichrome. Blue color indicates the formation of fibrous scar tissues in the infarction area.

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The International Space Station is the world's most extreme and expensive scientific laboratory. In its more than 20 years of operations it has housed thousands of experiments, providing fascinating insights into the effects of microgravity on the human body, cultured cells or various materials and chemical processes. Here are the most interesting findings that the space station delivered in 2021.

Stem cells are sometimes seen as the holy grail of future medicine. Capable of almost endlessly regenerating and turning themselves into all sorts of cells, stem cells are abundant in young bodies but lose their vigor as we age. There are various types of stem cells. Those found in embryos, also called the pluripotent stem cells, can give rise to all kinds of cells in the human body. But stem cells exist in adult bodies too, ensuring the ability of various organs to repair themselves.

A recent experiment flown on the International Space Station found that in the weightless environment, stem cells from the human heart improved their ability to regenerate, survive and proliferate.

The effects were observed in both adult and neonatal stem cells. The discovery, part of NASA's Cardiac Stem Cells research project, is good news for the future of regenerative medicine as it shows that it is possible to kick adult heart stem cells into better action. That is to increase their 'stemness', their ability to regenerate, proliferate and create new types of cells that a damaged organ might need. Regenerative medicine hopes to one day be able to engineer tissue to repair and replace failing organs and cells. The study was published in the International Journal of Molecular Sciences.

Related: What does space do to the human body? 29 studies investigate the effects of exploration

Microgravity is bad news for bones. The lack of mechanical loading tells the body to stop maintaining these important support structures since they don't seem to be needed. When astronauts return to Earth, they suffer from serious bone loss.

The good news is, that just like on Earth, exercising in space seems to keep the body fit, including the bones. A new study published in the British Journal of Sports Medicine revealed that crew members who increased their resistance training during their space missions were more likely to preserve their bone strength.

The study, part of NASA's Biochem Profile and the Canadian Space Agency's TBone investigations, also found that bone loss in some astronauts could be predicted by the elevation of certain biomarkers before their flight. These biomarkers, found in the astronauts' blood and urine, together with the astronauts' exercise history could help space surgeons identify astronauts at greater risk for bone loss.

Microbes can efficiently extract valuable metals from lunar and martian rocks in space, a recent experiment by the European Space Agency (ESA) revealed. The experiment, called Biorock, used microorganisms to extract the metal element vanadium from basalt, which can be commonly found on the moon and Mars.

The microbes extracted 283% more vanadium while on the space station than on Earth. Biomining is a cheaper and more environmentally friendly alternative to chemical extraction of important materials from ores, a process that usually relies on harsh chemicals and requires a lot of energy. Using biomining in space will surely come handy to future Mars and moon colonists as they will be able to get raw materials for making tools, spacecraft parts and other equipment.

A European instrument called the Atmosphere-Space Interactions Monitor (ASIM) has provided new insights into the genesis of some little understood phenomena in Earth's atmosphere. Used to study severe thunderstorms and their atmospheric effects, ASIM previously helped shed light on the generation of high-energy terrestrial gamma-ray flashes (TGFs), the most energetic natural phenomena on Earth that accompany lightings during thunderstorms.

But more recently, the instrument studied the so-called blue jets, which are essentially upward shooting bursts of lighting generated by disturbances of positively and negatively charged regions in the tops of the clouds. Blue jets, which get their characteristic blue color from nitrogen ions, can shoot up to altitudes of 30 miles (50 kilometers) in less than a second.

Scientists found that the blue jets are generated by "blue bangs," short discharges in the upper layers of storm clouds. The mechanism behind these blue jets appears to be somewhat different from that behind normal lightning that we can observe on the ground.

Astronauts on the International Space Station experimented with making cement in space and found that although it creates somewhat different microstructures than on Earth, it works. The experiment, called Microgravity Investigation of Cement Solidification (MICS), involved mixing cement powders with various additives and different amounts of water.

In the latest round of experiments, a mixture of tricalcium aluminate and gypsum showed interesting results.

In the future, these "made in space" cement blends could be used to build stations on Mars or the moon. Cement is used to make concrete, which has excellent shielding properties against cosmic radiation. It is also strong enough to protect against impacting meteorites.

And to make things easy, future Mars and moon colonists could actually 3D-print structures from concrete made from lunar and martian soils in a 3D printer similar to the Additive Manufacturing Facility that is currently on the space station.

New space station research has shown that the technology used to shield astronauts from dangerous space radiation can be made even more efficient in the future using a mineral called colemanite. This boron-rich mineral is a type of borax that forms as a deposit during evaporation of alkaline water.

An experiment by the Japan Aerospace Exploration Agency (JAXA) exposed several pieces of a polymer material to space conditions outside the International Space Station. The polymer sample treated with colemanite suffered almost no radiation damage and looked nearly indistinguishable from a sample that was not exposed to space. The researchers published their results in the Journal of Applied Polymer Science in July.

In the future, colemanite could be used to treat satellites, space station exteriors or even high altitude planes, NASA said in a statement.

Astronauts and cosmonauts in space frequently suffer from changes to the structure of their veins, especially in their legs. A study by the Russian space agency Roscosmos, however, found that these changes can be somewhat prevented by exercise and can be reversed post-flight if the space travellers have enough time off between missions.

The veins of the 11 cosmonauts that participated in this study, published in the journal Experimental and Theoretical Research, didn't show worse damage after the second flight compared to the first. The spacefarers had breaks of about 4 years between their missions.

Follow Tereza Pultarova on Twitter @TerezaPultarova. Follow us on Twitter @Spacedotcom and on Facebook.

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Introduction

Given the multi-lineage differentiation abilities of mesenchymal stem cells (MSCs) isolated from different tissues and organs, MSCs have been widely used in various medical fields, particularly regenerative medicine.13 The representative sources of MSCs are bone marrow, adipose, periodontal, muscle, and umbilical cord blood.410 Interestingly, slight differences have been reported in the characteristics of MSCs depending on the different sources, including their population in source tissues, immunosuppressive activities, proliferation, and resistance to cellular aging.11 Bone marrow-derived MSCs (BM-MSCs) are the most intensively studied and show clinically promising results for cartilage and bone regeneration.11 However, the isolation procedures for BM-MSCs are complicated because bone marrow contains a relatively small fraction of MSCs (0.0010.01% of the cells in bone marrow).12 Furthermore, bone marrow aspiration to harvest MSCs in human bones is a painful procedure and the slower proliferation rate of BM-MSCs is a clinical limitation.13 In comparison with BM-MSCs, adipose-derived MSCs (AD-MSCs) are relatively easy to collect and can produce up to 500 times the cell population of BM-MSCs.14 AD-MSCs showed a greater ability to regenerate damaged cartilage and bone tissues with increased immunosuppressive ability.14,15 Umbilical cord blood-derived MSCs (UC-MSCs) proliferate faster than BM-MSCs and are resistant to significant cellular aging.11

MSCs have been investigated and gained worldwide attention as potential therapeutic candidates for incurable diseases such as arthritis, spinal cord injury, and cardiac disease.3,1623 In particular, the inherent tropism of MSCs to inflammatory sites has been thoroughly studied.24 This inherent tropism, also known as homing ability, originates from the recognition of various chemokine sources in inflamed tissues, where profiled chemokines are continuously secreted and the MSCs migrate to the chemokines in a concentration-dependent manner.24 Rheumatoid arthritis (RA) is a representative inflammatory disease that primarily causes inflammation in the joints, and this long-term autoimmune disorder causes worsening pain and stiffness following rest. RA affects approximately 24.5 million people as of 2015, but only symptomatic treatments such as pain medications, steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), or slow-acting drugs that inhibit the rapid progression of RA, such as disease-modifying antirheumatic drugs (DMARDs) are currently available. However, RA drugs have adverse side effects, including hepatitis, osteoporosis, skeletal fracture, steroid-induced arthroplasty, Cushings syndrome, gastrointestinal (GI) intolerance, and bleeding.2527 Thus, MSCs are rapidly emerging as the next generation of arthritis treatment because they not only recognize and migrate toward chemokines secreted in the inflamed joints but also regulate inflammatory progress and repair damaged cells.28

However, MSCs are associated with many challenges that need to be overcome before they can be used in clinical settings.2931 One of the main challenges is the selective accumulation of systemically administered MSCs in the lungs and liver when they are administered intravenously, leading to insufficient concentrations of MSCs in the target tissues.32,33 In addition, most of the administered MSCs are typically initially captured by macrophages in the lungs, liver, and spleen.3234 Importantly, the viability and migration ability of MSCs injected in vivo differed from results previously reported as favorable therapeutic effects and migration efficiency in vitro.35

To improve the delivery of MSCs, researchers have focused on chemokines, which are responsible for MSCs ability to move.36 The chemokine receptors are the key proteins on MSCs that recognize chemokines, and genetic engineering of MSCs to overexpress the chemokine receptor can improve the homing ability, thus enhancing their therapeutic efficacy.37 Genetic engineering is a convenient tool for modifying native or non-native genes, and several technologies for genetic engineering exist, including genome editing, gene knockdown, and replacement with various vectors.38,39 However, safety issues that prevent clinical use persist, for example, genome integration, off-target effects, and induction of immune response.40 In this regard, MSC mimicking nanoencapsulations can be an alternative strategy for maintaining the homing ability of MSCs and overcoming the current safety issues.4143 Nanoencapsulation involves entrapping the core nanoparticles of solids or liquids within nanometer-sized capsules of secondary materials.44

MSC mimicking nanoencapsulation uses the MSC membrane fraction as the capsule and targeting molecules, that is chemokine receptors, with several types of nanoparticles, as the core.45,46 MSC mimicking nanoencapsulation consists of MSC membrane-coated nanoparticles, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes. Nano drug delivery is an emerging field that has attracted significant interest due to its unique characteristics and paved the way for several unique applications that might solve many problems in medicine. In particular, the nanoscale size of nanoparticles (NPs) enhances cellular uptake and can optimize intracellular pathways due to their intrinsic physicochemical properties, and can therefore increase drug delivery to target tissues.47,48 However, the inherent targeting ability resulting from the physicochemical properties of NPs is not enough to target specific tissues or damaged tissues, and additional studies on additional ligands that can bind to surface receptors on target cells or tissues have been performed to improve the targeting ability of NPs.49 Likewise, nanoencapsulation with cell membranes with targeting molecules and encapsulation of the core NPs with cell membranes confer the targeting ability of the source cell to the NPs.50,51 Thus, MSC mimicking nanoencapsulation can mimic the superior targeting ability of MSCs and confer the advantages of each core NP. In addition, MSC mimicking nanoencapsulations have improved circulation time and camouflaging from phagocytes.52

This review discusses the mechanism of MSC migration to inflammatory sites, addresses the potential strategy for improving the tropism of MSCs using genetic engineering, and discusses the promising therapeutic agent, MSC mimicking nanoencapsulations.

The MSC migration mechanism can be exploited for diverse clinical applications.53 The MSC migration mechanism can be divided into five stages: rolling by selectin, activation of MSCs by chemokines, stopping cell rolling by integrin, transcellular migration, and migration to the damaged site (Figure 1).54,55 Chemokines are secreted naturally by various cells such as tumor cells, stromal cells, and inflammatory cells, maintaining high chemokine concentrations in target cells at the target tissue and inducing signal cascades.5658 Likewise, MSCs express a variety of chemokine receptors, allowing them to migrate and be used as new targeting vectors.5961 MSC migration accelerates depending on the concentration of chemokines, which are the most important factors in the stem cell homing mechanism.62,63 Chemokines consist of various cytokine subfamilies that are closely associated with the migration of immune cells. Chemokines are divided into four classes based on the locations of the two cysteine (C) residues: CC-chemokines, CXC-chemokine, C-chemokine, and CX3 Chemokine.64,65 Each chemokine binds to various MSC receptors and the binding induces a chemokine signaling cascade (Table 1).56,66

Table 1 Chemokine and Chemokine Receptors for Different Chemokine Families

Figure 1 Representation of stem cell homing mechanism.

The mechanisms underlying MSC and leukocyte migration are similar in terms of their migratory dynamics.55 P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) are major proteins involved in leukocyte migration that interact with P-selectin and E-selectin present in vascular endothelial cells. However, these promoters are not present in MSCs (Figure 2).53,67

Figure 2 Differences in adhesion protein molecules between leukocytes and mesenchymal stem cells during rolling stages and rolling arrest stage of MSC. (A) The rolling stage of leukocytes starts with adhesion to endothelium with ESL-1 and PSGL-1 on leukocytes. (B) The rolling stage of MSC starts with the adhesion to endothelium with Galectin-1 and CD24 on MSC, and the rolling arrest stage was caused by chemokines that were encountered in the rolling stage and VLA-4 with a high affinity for VACM present in endothelial cells.

Abbreviations: ESL-1, E-selectin ligand-1; PSGL-1, P-selectin glycoprotein ligand-1 VLA-4, very late antigen-4; VCAM, vascular cell adhesion molecule-1.

The initial rolling is facilitated by selectins expressed on the surface of endothelial cells. Various glycoproteins on the surface of MSCs can bind to the selectins and continue the rolling process.68 However, the mechanism of binding of the glycoprotein on MSCs to the selectins is still unclear.69,70 P-selectins and E-selectins, major cell-cell adhesion molecules expressed by endothelial cells, adhere to migrated cells adjacent to endothelial cells and can trigger the rolling process.71 For leukocyte migration, P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) expressed on the membranes of leukocytes interact with P-selectins and E-selectins on the endothelial cells, initiating the process.72,73 As already mentioned, MSCs express neither PSGL-1 nor ESL-1. Instead, they express galectin-1 and CD24 on their surfaces, and these bind to E-selectin or P-selectin (Figure 2).7476

In the migratory activation step, MSC receptors are activated in response to inflammatory cytokines, including CXCL12, CXCL8, CXCL4, CCL2, and CCL7.77 The corresponding activation of chemokine receptors of MSCs in response to inflammatory cytokines results in an accumulation of MSCs.58,78 For example, inflamed tissues release inflammatory cytokines,79 and specifically, fibroblasts release CXCL12, which further induces the accumulation of MSCs through ligandreceptor interaction after exposure to hypoxia and cytokine-rich environments in the rat model of inflammation.7982 Previous studies have reported that overexpressing CXCR4, which is a receptor to recognize CXCL12, in MSCs improves the homing ability of MSCs toward inflamed sites.83,84 In short, cytokines are significantly involved in the homing mechanism of MSCs.53

The rolling arrest stage is facilitated by integrin 41 (VLA-4) on MSC.85 VLA-4 is expressed by MSCs which are first activated by CXCL-12 and TNF- chemokines, and activated VLA-4 binds to VCAM-1 expressed on endothelial cells to stop the rotational movement (Figure 2).86,87

Karp et al categorized the migration of MSCs as either systemic homing or non-systemic homing. Systemic homing refers to the process of migration through blood vessels and then across the vascular endothelium near the inflamed site.67,88 The process of migration after passing through the vessels or local injection is called non-systemic homing. In non-systemic migration, stem cells migrate through a chemokine concentration gradient (Figure 3).89 MSCs secrete matrix metalloproteinases (MMPs) during migration. The mechanism underlying MSC migration is currently undefined but MSC migration can be advanced by remodeling the matrix through the secretion of various enzymes.9093 The migration of MSCs to the damaged area is induced by chemokines released from the injured site, such as IL-8, TNF-, insulin-like growth factor (IGF-1), and platelet-derived growth factors (PDGF).9496 MSCs migrate toward the damaged area following a chemokine concentration gradient.87

Figure 3 Differences between systemic and non-systemic homing mechanisms. Both systemic and non-systemic homing to the extracellular matrix and stem cells to their destination, MSCs secrete MMPs and remodel the extracellular matrix.

Abbreviation: MMP, matrix metalloproteinase.

RA is a chronic inflammatory autoimmune disease characterized by distinct painful stiff joints and movement disorders.97 RA affects approximately 1% of the worlds population.98 RA is primarily induced by macrophages, which are involved in the innate immune response and are also involved in adaptive immune responses, together with B cells and T cells.99 Inflammatory diseases are caused by high levels of inflammatory cytokines and a hypoxic low-pH environment in the joints.100,101 Fibroblast-like synoviocytes (FLSs) and accumulated macrophages and neutrophils in the synovium of inflamed joints also express various chemokines.102,103 Chemokines from inflammatory reactions can induce migration of white blood cells and stem cells, which are involved in angiogenesis around joints.101,104,105 More than 50 chemokines are present in the rheumatoid synovial membrane (Table 2). Of the chemokines in the synovium, CXCL12, MIP1-a, CXCL8, and PDGF are the main ones that attract MSCs.106 In the RA environment, CXCL12, a ligand for CXCR4 on MSCs, had 10.71 times higher levels of chemokines than in the normal synovial cell environment. MIP-1a, a chemokine that gathers inflammatory cells, is a ligand for CCR1, which is normally expressed on MSC.107,108 CXCL8 is a ligand for CXCR1 and CXCR2 on MSCs and induces the migration of neutrophils and macrophages, leading to ROS in synovial cells.59 PDGF is a regulatory peptide that is upregulated in the synovial tissue of RA patients.109 PDGF induces greater MSC migration than CXCL12.110 Importantly, stem cells not only have the homing ability to inflamed joints but also have potential as cell therapy with the anti-apoptotic, anti-catabolic, and anti-fibrotic effect of MSC.111 In preclinical trials, MSC treatment has been extensively investigated in collagen-induced arthritis (CIA), a common autoimmune animal model used to study RA. In the RA model, MSCs downregulated inflammatory cytokines such as IFN-, TNF-, IL-4, IL-12, and IL1, and antibodies against collagen, while anti-inflammatory cytokines, such as tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF-), IL-10, and IL-6, were upregulated.112116

Table 2 Rheumatoid Arthritis (RA) Chemokines Present in the Pathological Environment and Chemokine Receptors Present in Mesenchymal Stem Cells

Genetic engineering can improve the therapeutic potential of MSCs, including long-term survival, angiogenesis, differentiation into specific lineages, anti- and pro-inflammatory activity, and migratory properties (Figure 4).117,118 Although MSCs already have an intrinsic homing ability, the targeting ability of MSCs and their derivatives, such as membrane vesicles, which are utilized to produce MSC mimicking nanoencapsulation, can be enhanced.118 The therapeutic potential of MSCs can be magnified by reprogramming MSCs via upregulation or downregulation of their native genes, resulting in controlled production of the target protein, or by introducing foreign genes that enable MSCs to express native or non-native products, for example, non-native soluble tumor necrosis factor (TNF) receptor 2 can inhibit TNF-alpha signaling in RA therapies.28

Figure 4 Genetic engineering of mesenchymal stem cells to enhance therapeutic efficacy.

Abbreviations: Sfrp2, secreted frizzled-related protein 2; IGF1, insulin-like growth factor 1; IL-2, interleukin-2; IL-12, interleukin-12; IFN-, interferon-beta; CX3CL1, C-X3-C motif chemokine ligand 1; VEGF, vascular endothelial growth factor; HGF, human growth factor; FGF, fibroblast growth factor; IL-10, interleukin-10; IL-4, interleukin-4; IL18BP, interleukin-18-binding protein; IFN-, interferon-alpha; SDF1, stromal cell-derived factor 1; CXCR4, C-X-C motif chemokine receptor 4; CCR1, C-C motif chemokine receptor 1; BMP2, bone morphogenetic protein 2; mHCN2, mouse hyperpolarization-activated cyclic nucleotide-gated.

MSCs can be genetically engineered using different techniques, including by introducing particular genes into the nucleus of MSCs or editing the genome of MSCs (Figure 5).119 Foreign genes can be transferred into MSCs using liposomes (chemical method), electroporation (physical method), or viral delivery (biological method). Cationic liposomes, also known as lipoplexes, can stably compact negatively charged nucleic acids, leading to the formation of nanomeric vesicular structure.120 Cationic liposomes are commonly produced with a combination of a cationic lipid such as DOTAP, DOTMA, DOGS, DOSPA, and neutral lipids, such as DOPE and cholesterol.121 These liposomes are stable enough to protect their bound nucleic acids from degradation and are competent to enter cells via endocytosis.120 Electroporation briefly creates holes in the cell membrane using an electric field of 1020 kV/cm, and the holes are then rapidly closed by the cells membrane repair mechanism.122 Even though the electric shock induces irreversible cell damage and non-specific transport into the cytoplasm leads to cell death, electroporation ensures successful gene delivery regardless of the target cell or organism. Viral vectors, which are derived from adenovirus, adeno-associated virus (AAV), or lentivirus (LV), have been used to introduce specific genes into MSCs. Recombinant lentiviral vectors are the most widely used systems due to their high tropism to dividing and non-dividing cells, transduction efficiency, and stable expression of transgenes in MSCs, but the random genome integration of transgenes can be an obstacle in clinical applications.123 Adenovirus and AAV systems are appropriate alternative strategies because currently available strains do not have broad genome integration and a strong immune response, unlike LV, thus increasing success and safety in clinical trials.124 As a representative, the Oxford-AstraZeneca COVID-19 vaccine, which has been authorized in 71 countries as a vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread globally and led to the current pandemic, transfers the spike protein gene using an adenovirus-based viral vector.125 Furthermore, there are two AAV-based gene therapies: Luxturna for rare inherited retinal dystrophy and Zolgensma for spinal muscular atrophy.126

Figure 5 Genetic engineering techniques used in the production of bioengineered mesenchymal stem cells.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 were recently used for genome editing and modification because of their simpler design and higher efficiency for genome editing, however, there are safety issues such as off-target effects that induce mutations at sites other than the intended target site.127 The foreign gene is then commonly transferred into non-integrating forms such as plasmid DNA and messenger RNA (mRNA).128

The gene expression machinery can also be manipulated at the cytoplasmic level through RNA interference (RNAi) technology, inhibition of gene expression, or translation using neutralizing targeted mRNA molecules with sequence-specific small RNA molecules such as small interfering RNA (siRNA) or microRNA (miRNA).129 These small RNAs can form enzyme complexes that degrade mRNA molecules and thus decrease their activity by inhibiting translation. Moreover, the pre-transcriptional silencing mechanism of RNAi can induce DNA methylation at genomic positions complementary to siRNA or miRNA with enzyme complexes.

CXC chemokine receptor 4 (CXCR4) is one of the most potent chemokine receptors that is genetically engineered to enhance the migratory properties of MSCs.130 CXCR4 is a chemokine receptor specific for stromal-derived factor-1 (SDF-1), also known as CXC motif chemokine 12 (CXCL12), which is produced by damaged tissues, such as the area of inflammatory bone destruction.131 Several studies on engineering MSCs to increase the expression of the CXCR4 gene have reported a higher density of the CXCR4 receptor on their outer cell membrane and effectively increased the migration of MSCs toward SDF-1.83,132,133 CXC chemokine receptor 7 (CXCR7) also had a high affinity for SDF-1, thus the SDF-1/CXCR7 signaling axis was used to engineer the MSCs.134 CXCR7-overexpressing MSCs in a cerebral ischemia-reperfusion rat hippocampus model promoted migration based on an SDF-1 gradient, cooperating with the SDF-1/CXCR4 signaling axis (Figure 6).37

Figure 6 Engineered mesenchymal stem cells with enhanced migratory abilities.

Abbreviations: CXCR4, C-X-C motif chemokine receptor 4; CXCR7, C-X-C motif chemokine receptor 7; SDF1, stromal cell-derived factor 1; CXCR1, C-X-C motif chemokine receptor 1; IL-8, interleukin-8; Aqp1, aquaporin 1; FAK, focal adhesion kinase.

CXC chemokine receptor 1 (CXCR1) enhances MSC migratory properties.59 CXCR1 is a receptor for IL-8, which is the primary cytokine involved in the recruitment of neutrophils to the site of damage or infection.135 In particular, the IL-8/CXCR1 axis is a key factor for the migration of MSCs toward human glioma cell lines, such as U-87 MG, LN18, U138, and U251, and CXCR1-overexpressing MSCs showed a superior capacity to migrate toward glioma cells and tumors in mice bearing intracranial human gliomas.136

The migratory properties of MSCs were also controlled via aquaporin-1 (Aqp1), which is a water channel molecule that transports water across the cell membrane and regulates endothelial cell migration.137 Aqp1-overexpressing MSCs showed enhanced migration to fracture gap of a rat fracture model with upregulated focal adhesion kinase (FAK) and -catenin, which are important regulators of cell migration.138

Nur77, also known as nerve growth factor IB or NR4A1, and nuclear receptor-related 1 (Nurr1), can play a role in improving the migratory capabilities of MSCs.139,140 The migrating MSCs expressed higher levels of Nur77 and Nurr1 than the non-migrating MSCs, and overexpression of these two nuclear receptors functioning as transcription factors enhanced the migration of MSCs toward SDF-1. The migration of cells is closely related to the cell cycle, and normally, cells in the late S or G2/M phase do not migrate.141 The overexpression of Nur77 and Nurr1 increased the proportion of MSCs in the G0/G1-phase similar to the results of migrating MSCs had more cells in the G1-phase.

MSC mimicking nanoencapsulations are nanoparticles combined with MSC membrane vesicles and these NPs have the greatest advantages as drug delivery systems due to the sustained homing ability of MSCs as well as the advantages of NPs. Particles sized 10150 nm have great advantages in drug delivery systems because they can pass more freely through the cell membrane by the interaction with biomolecules, such as clathrin and caveolin, to facilitate uptake across the cell membrane compared with micron-sized materials.142,143 Various materials have been used to formulate NPs, including silica, polymers, metals, and lipids.144,145 NPs have an inherent ability, called passive targeting, to accumulate at specific sites based on their physicochemical properties such as size, surface charge, surface hydrophilicity, and geometry.146148 However, physicochemical properties are not enough to target specific tissues or damaged tissues, and thus active targeting is a clinically approved strategy involving the addition of ligands that can bind to surface receptors on target cells or tissues.149,150 MSC mimicking nanoencapsulation uses natural or genetically engineered MSC membranes to coat synthetic NPs, producing artificial ectosomes and fusing them with liposomes to increase their targeting ability (Figure 7).151 Especially, MSCs have been studied for targeting inflammation and regenerative drugs, and the mechanism and efficacy of migration toward inflamed tissues have been actively investigated.152 MSC mimicking nanoencapsulation can mimic the well-known migration ability of MSCs and can be equally utilized without safety issues from the direct application of using MSCs. Furthermore, cell membrane encapsulations have a wide range of functions, including prolonged blood circulation time and increased active targeting efficacy from the source cells.153,154 MSC mimicking encapsulations enter recipient cells using multiple pathways.155 MSC mimicking encapsulations can fuse directly with the plasma membrane and can also be taken up through phagocytosis, micropinocytosis, and endocytosis mediated by caveolin or clathrin.156 MSC mimicking encapsulations can be internalized in a highly cell type-specific manner that depends on the recognition of membrane surface molecules by the cell or tissue.157 For example, endothelial colony-forming cell (ECFC)-derived exosomes were shown CXCR4/SDF-1 interaction and enhanced delivery toward the ischemic kidney, and Tspan8-alpha4 complex on lymph node stroma derived extracellular vesicles induced selective uptake by endothelial cells or pancreatic cells with CD54, serving as a major ligand.158,159 Therefore, different source cells may contain protein signals that serve as ligands for other cells, and these receptorligand interactions maximized targeted delivery of NPs.160 This natural mechanism inspired the application of MSC membranes to confer active targeting to NPs.

Figure 7 Mesenchymal stem cell mimicking nanoencapsulation.

Cell membrane-coated NPs (CMCNPs) are biomimetic strategies developed to mimic the properties of cell membranes derived from natural cells such as erythrocytes, white blood cells, cancer cells, stem cells, platelets, or bacterial cells with an NP core.161 Core NPs made of polymer, silica, and metal have been evaluated in attempts to overcome the limitations of conventional drug delivery systems but there are also issues of toxicity and reduced biocompatibility associated with the surface properties of NPs.162,163 Therefore, only a small number of NPs have been approved for medical application by the FDA.164 Coating with cell membrane can enhance the biocompatibility of NPs by improving immune evasion, enhancing circulation time, reducing RES clearance, preventing serum protein adsorption by mimicking cell glycocalyx, which are chemical determinants of self at the surfaces of cells.151,165 Furthermore, the migratory properties of MSCs can also be transferred to NPs by coating them with the cell membrane.45 Coating NPs with MSC membranes not only enhances biocompatibility but also maximizes the therapeutic effect of NPs by mimicking the targeting ability of MSCs.166 Cell membrane-coated NPs are prepared in three steps: extraction of cell membrane vesicles from the source cells, synthesis of the core NPs, and fusion of the membrane vesicles and core NPs to produce cell membrane-coated NPs (Figure 8).167 Cell membrane vesicles, including extracellular vesicles (EVs), can be harvested through cell lysis, mechanical disruption, and centrifugation to isolate, purify the cell membrane vesicles, and remove intracellular components.168 All the processes must be conducted under cold conditions, with protease inhibitors to minimize the denaturation of integral membrane proteins. Cell lysis, which is classically performed using mechanical lysis, including homogenization, sonication, or extrusion followed by differential velocity centrifugation, is necessary to remove intracellular components. Cytochalasin B (CB), a drug that affects cytoskeletonmembrane interactions, induces secretion of membrane vesicles from source cells and has been used to extract the cell membrane.169 The membrane functions of the source cells are preserved in CB-induced vesicles, forming biologically active surface receptors and ion pumps.170 Furthermore, CB-induced vesicles can encapsulate drugs and NPs successfully, and the vesicles can be harvested by centrifugation without a purification step to remove nuclei and cytoplasm.171 Clinically translatable membrane vesicles require scalable production of high volumes of homogeneous vesicles within a short period. Although mechanical methods (eg, shear stress, ultrasonication, or extrusion) are utilized, CB-induced vesicles have shown potential for generating membrane encapsulation for nano-vectors.168 The advantages of CB-induced vesicles versus other methods are compared in Table 3.

Table 3 Comparison of Membrane Vesicle Production Methods

Figure 8 MSC membrane-coated nanoparticles.

Abbreviations: EVs, extracellular vesicles; NPs, nanoparticles.

After extracting cell membrane vesicles, synthesized core NPs are coated with cell membranes, including surface proteins.172 Polymer NPs and inorganic NPs are adopted as materials for the core NPs of CMCNPs, and generally, polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), chitosan, and gelatin are used. PLGA has been approved by FDA is the most common polymer of NPs.173 Biodegradable polymer NPs have gained considerable attention in nanomedicine due to their biocompatibility, nontoxic properties, and the ability to modify their surface as a drug carrier.174 Inorganic NPs are composed of gold, iron, copper, and silicon, which have hydrophilic, biocompatible, and highly stable properties compared with organic materials.175 Furthermore, some photosensitive inorganic NPs have the potential for use in photothermal therapy (PTT) and photodynamic therapy (PDT).176 The fusion of cell membrane vesicles and core NPs is primarily achieved via extrusion or sonication.165 Cell membrane coating of NPs using mechanical extrusion is based on a different-sized porous membrane where core NPs and vesicles are forced to generate vesicle-particle fusion.177 Ultrasonic waves are applied to induce the fusion of vesicles and NPs. However, ultrasonic frequencies need to be optimized to improve fusion efficiency and minimize drug loss and protein degradation.178

CMCNPs have extensively employed to target and treat cancer using the membranes obtained from red blood cell (RBC), platelet and cancer cell.165 In addition, membrane from MSC also utilized to target tumor and ischemia with various types of core NPs, such as MSC membrane coated PLGA NPs targeting liver tumors, MSC membrane coated gelatin nanogels targeting HeLa cell, MSC membrane coated silica NPs targeting HeLa cell, MSC membrane coated PLGA NPs targeting hindlimb ischemia, and MSC membrane coated iron oxide NPs for targeting the ischemic brain.179183 However, there are few studies on CMCNPs using stem cells for the treatment of arthritis. Increased targeting ability to arthritis was introduced using MSC-derived EVs and NPs.184,185 MSC membrane-coated NPs are proming strategy for clearing raised concerns from direct use of MSC (with or without NPs) in terms of toxicity, reduced biocompatibility, and poor targeting ability of NPs for the treatment of arthritis.

Exosomes are natural NPs that range in size from 40 nm to 120 nm and are derived from the multivesicular body (MVB), which is an endosome defined by intraluminal vesicles (ILVs) that bud inward into the endosomal lumen, fuse with the cell surface, and are then released as exosomes.186 Because of their ability to express receptors on their surfaces, MSC-derived exosomes are also considered potential candidates for targeting.187 Exosomes are commonly referred to as intracellular communication molecules that transfer various compounds through physiological mechanisms such as immune response, neural communication, and antigen presentation in diseases such as cancer, cardiovascular disease, diabetes, and inflammation.188

However, there are several limitations to the application of exosomes as targeted therapeutic carriers. First, the limited reproducibility of exosomes is a major challenge. In this field, the standardized techniques for isolation and purification of exosomes are lacking, and conventional methods containing multi-step ultracentrifugation often lead to contamination of other types of EVs. Furthermore, exosomes extracted from cell cultures can vary and display inconsistent properties even when the same type of donor cells were used.189 Second, precise characterization studies of exosomes are needed. Unknown properties of exosomes can hinder therapeutic efficiencies, for example, when using exosomes as cancer therapeutics, the use of cancer cell-derived exosomes should be avoided because cancer cell-derived exosomes may contain oncogenic factors that may contribute to cancer progression.190 Finally, cost-effective methods for the large-scale production of exosomes are needed for clinical application. The yield of exosomes is much lower than EVs. Depending on the exosome secretion capacity of donor cells, the yield of exosomes is restricted, and large-scale cell culture technology for the production of exosomes is high difficulty and costly and isolation of exosomes is the time-consuming and low-efficient method.156

Ectosome is an EV generated by outward budding from the plasma membrane followed by pinching off and release to the extracellular parts. Recently, artificially produced ectosome utilized as an alternative to exosomes in targeted therapeutics due to stable productivity regardless of cell type compared with conventional exosome. Artificial ectosomes, containing modified cargo and targeting molecules have recently been introduced for specific purposes (Figure 9).191,192 Artificial ectosomes are typically prepared by breaking bigger cells or cell membrane fractions into smaller ectosomes, similar size to natural exosomes, containing modified cargo such as RNA molecules, which control specific genes, and chemical drugs such as anticancer drugs.193 Naturally secreted exosomes in conditioned media from modified source cells can be harvested by differential ultracentrifugation, density gradients, precipitation, filtration, and size exclusion chromatography for exosome separation.194 Even though there are several commercial kits for isolating exosomes simply and easily, challenges in compliant scalable production on a large scale, including purity, homogeneity, and reproducibility, have made it difficult to use naturally secreted exosomes in clinical settings.195 Therefore, artificially produced ectosomes are appropriate for use in clinical applications, with novel production methods that can meet clinical production criteria. Production of artificially produced ectosomes begins by breaking the cell membrane fraction of cultured cells and then using them to produce cell membrane vesicles to form ectosomes. As mentioned above, cell membrane vesicles are extracted from source cells in several ways, and cell membrane vesicles are extracted through polycarbonate membrane filters to reduce the mean size to a size similar to that of natural exosomes.196 Furthermore, specific microfluidic devices mounted on microblades (fabricated in silicon nitride) enable direct slicing of living cells as they flow through the hydrophilic microchannels of the device.197 The sliced cell fraction reassembles and forms ectosomes. There are several strategies for loading exogenous therapeutic cargos such as drugs, DNA, RNA, lipids, metabolites, and proteins, into exosomes or artificial ectosomes in vitro: electroporation, incubation for passive loading of cargo or active loading with membrane permeabilizer, freeze and thaw cycles, sonication, and extrusion.198 In addition, protein or RNA molecules can be loaded by co-expressing them in source cells via bio-engineering, and proteins designed to interact with the protein inside the cell membrane can be loaded actively into exosomes or artificial ectosomes.157 Targeting molecules at the surface of exosomes or artificial ectosomes can also be engineered in a manner similar to the genetic engineering of MSCs.

Figure 9 Mesenchymal stem cell-derived exosomes and artificial ectosomes. (A) Wound healing effect of MSC-derived exosomes and artificial ectosomes,231 (B) treatment of organ injuries by MSC-derived exosomes and artificial ectosomes,42,232234 (C) anti-cancer activity of MSC-derived exosomes and artificial ectosomes.200,202,235

Most of the exosomes derived from MSCs for drug delivery have employed miRNAs or siRNAs, inhibiting translation of specific mRNA, with anticancer activity, for example, miR-146b, miR-122, and miR-379, which are used for cancer targeting by membrane surface molecules on MSC-derived exosomes.199201 Drugs such as doxorubicin, paclitaxel, and curcumin were also loaded into MSC-derived exosomes to target cancer.202204 However, artificial ectosomes derived from MSCs as arthritis therapeutics remains largely unexplored area, while EVs, mixtures of natural ectosomes and exosomes, derived from MSCs have studied in the treatment of arthritis.184 Artificial ectosomes with intrinsic tropism from MSCs plus additional targeting ability with engineering increase the chances of ectosomes reaching target tissues with ligandreceptor interactions before being taken up by macrophages.205 Eventually, this will decrease off-target binding and side effects, leading to lower therapeutic dosages while maintaining therapeutic efficacy.206,207

Liposomes are spherical vesicles that are artificially synthesized through the hydration of dry phospholipids.208 The clinically available liposome is a lipid bilayer surrounding a hollow core with a diameter of 50150 nm. Therapeutic molecules, such as anticancer drugs (doxorubicin and daunorubicin citrate) or nucleic acids, can be loaded into this hollow core for delivery.209 Due to their amphipathic nature, liposomes can load both hydrophilic (polar) molecules in an aqueous interior and hydrophobic (nonpolar) molecules in the lipid membrane. They are well-established biomedical applications and are the most common nanostructures used in advanced drug delivery.210 Furthermore, liposomes have several advantages, including versatile structure, biocompatibility, low toxicity, non-immunogenicity, biodegradability, and synergy with drugs: targeted drug delivery, reduction of the toxic effect of drugs, protection against drug degradation, and enhanced circulation half-life.211 Moreover, surfaces can be modified by either coating them with a functionalized polymer or PEG chains to improve targeted delivery and increase their circulation time in biological systems.212 Liposomes have been investigated for use in a wide variety of therapeutic applications, including cancer diagnostics and therapy, vaccines, brain-targeted drug delivery, and anti-microbial therapy. A new approach was recently proposed for providing targeting features to liposomes by fusing them with cell membrane vesicles, generating molecules called membrane-fused liposomes (Figure 10).213 Cell membrane vesicles retain the surface membrane molecules from source cells, which are responsible for efficient tissue targeting and cellular uptake by target cells.214 However, the immunogenicity of cell membrane vesicles leads to their rapid clearance by macrophages in the body and their low drug loading efficiencies present challenges for their use as drug delivery systems.156 However, membrane-fused liposomes have advantages of stability, long half-life in circulation, and low immunogenicity due to the liposome, and the targeting feature of cell membrane vesicles is completely transferred to the liposome.215 Furthermore, the encapsulation efficiencies of doxorubicin were similar when liposomes and membrane-fused liposomes were used, indicating that the relatively high drug encapsulation capacity of liposomes was maintained during the fusion process.216 Combining membrane-fused liposomes with macrophage-derived membrane vesicles showed differential targeting and cytotoxicity against normal and cancerous cells.217 Although only a few studies have been conducted, these results corroborate that membrane-fused liposomes are a potentially promising future drug delivery system with increased targeting ability. MSCs show intrinsic tropism toward arthritis, and further engineering and modification to enhance their targeting ability make them attractive candidates for the development of drug delivery systems. Fusing MSC exosomes with liposomes, taking advantage of both membrane vesicles and liposomes, is a promising technique for future drug delivery systems.

Figure 10 Mesenchymal stem cell membrane-fused liposomes.

MSCs have great potential as targeted therapies due to their greater ability to home to targeted pathophysiological sites. The intrinsic ability to home to wounds or to the tumor microenvironment secreting inflammatory mediators make MSCs and their derivatives targeting strategies for cancer and inflammatory disease.218,219 Contrary to the well-known homing mechanisms of various blood cells, it is still not clear how homing occurs in MSCs. So far, the mechanism of MSC tethering, which connects long, thin cell membrane cylinders called tethers to the adherent area for migration, has not been clarified. Recent studies have shown that galectin-1, VCAM-1, and ICAM are associated with MSC tethering,53,220 but more research is needed to accurately elucidate the tethering mechanism of MSCs. MSC chemotaxis is well defined and there is strong evidence relating it to the homing ability of MSCs.53 Chemotaxis involves recognizing chemokines through chemokine receptors on MSCs and migrating to chemokines in a gradient-dependent manner.221 RA, a representative inflammatory disease, is associated with well-profiled chemokines such as CXCR1, CXCR4, and CXCR7, which are recognized by chemokine receptors on MSCs. In addition, damaged joints in RA continuously secrete cytokines until they are treated, giving MSCs an advantage as future therapeutic agents for RA.222 However, there are several obstacles to utilizing MSCs as RA therapeutics. In clinical settings, the functional capability of MSCs is significantly affected by the health status of the donor patient.223 MSC yield is significantly reduced in patients undergoing steroid-based treatment and the quality of MSCs is dependent on the donors age and environment.35 In addition, when MSCs are used clinically, cryopreservation and defrosting are necessary, but these procedures shorten the life span of MSCs.224 Therefore, NPs mimicking MSCs are an alternative strategy for overcoming the limitations of MSCs. Additionally, further engineering and modification of MSCs can enhance the therapeutic effect by changing the targeting molecules and loaded drugs. In particular, upregulation of receptors associated with chemotaxis through genetic engineering can confer the additional ability of MSCs to home to specific sites, while the increase in engraftment maximizes the therapeutic effect of MSCs.36,225

Furthermore, there are several methods that can be used to exploit the targeting ability of MSCs as drug delivery systems. MSCs mimicking nanoencapsulation, which consists of MSC membrane-coated NPs, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes, can mimic the targeting ability of MSCs while retaining the advantages of NPs. MSC-membrane-coated NPs are synthesized using inorganic or polymer NPs and membranes from MSCs to coat inner nanosized structures. Because they mimic the biological characteristics of MSC membranes, MSC-membrane-coated NPs can not only escape from immune surveillance but also effectively improve targeting ability, with combined functions of the unique properties of core NPs and MSC membranes.226 Exosomes are also an appropriate candidate for use in MSC membranes, utilizing these targeting abilities. However, natural exosomes lack reproducibility and stable productivity, thus artificial ectosomes with targeting ability produced via synthetic routes can increase the local concentration of ectosomes at the targeted site, thereby reducing toxicity and side effects and maximizing therapeutic efficacy.156 MSC membrane-fused liposomes, a novel system, can also transfer the targeting molecules on the surface of MSCs to liposomes; thus, the advantages of liposomes are retained, but with targeting ability. With advancements in nanotechnology of drug delivery systems, the research in cell-mimicking nanoencapsulation will be very useful. Efficient drug delivery systems fundamentally improve the quality of life of patients with a low dose of medication, low side effects, and subsequent treatment of diseases.227 However, research on cell-mimicking nanoencapsulation is at an early stage, and several problems need to be addressed. To predict the nanotoxicity of artificially synthesized MSC mimicking nanoencapsulations, interactions between lipids and drugs, drug release mechanisms near the targeted site, in vivo compatibility, and immunological physiological studies must be conducted before clinical application.

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2019M3A9H1103690), by the Gachon University Gil Medical Center (FRD2021-03), and by the Gachon University research fund of 2020 (GGU-202008430004).

The authors report no conflicts of interest in this work.

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Stem Cell Mimicking Nanoencapsulation for Targeting Arthrit | IJN - Dove Medical Press

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1Regenerative Medicine Centre, Arabian Gulf University, Manama, Bahrain; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain

Introduction: Stroke is a leading cause of death and disability worldwide. The disease is caused by reduced blood flow into the brain resulting in the sudden death of neurons. Limited spontaneous recovery might occur after stroke or brain injury, stem cell-based therapies have been used to promote these processes as there are no drugs currently on the market to promote brain recovery or neurogenesis. Adult stem cells (ASCs) have shown the ability of differentiation and regeneration and are well studied in literature. ASCs have also demonstrated safety in clinical application and, therefore, are currently being investigated as a promising alternative intervention for the treatment of stroke.Methods: Eleven studies have been systematically selected and reviewed to determine if autologous adult stem cells are effective in the treatment of stroke. Collectively, 368 patients were enrolled across the 11 trials, out of which 195 received stem cell transplantation and 173 served as control. Using data collected from the clinical outcomes, a broad comparison and a meta-analysis were conducted by comparing studies that followed a similar study design.Results: Improvement in patients clinical outcomes was observed. However, the overall results showed no clinical significance in patients transplanted with stem cells than the control population.Conclusion: Most of the trials were early phase studies that focused on safety rather than efficacy. Stem cells have demonstrated breakthrough results in the field of regenerative medicine. Therefore, study design could be improved in the future by enrolling a larger patient population and focusing more on localized delivery rather than intravenous transplantation. Trials should also introduce a more standardized method of analyzing and reporting clinical outcomes to achieve a better comparable outcome and possibly recognize the full potential that these cells have to offer.

Keywords: adult stem cells, autologous, neurogenesis, inflammation, clinical application, stroke, stroke recovery, systematic review, meta-analysis

Stroke is the second leading cause of death worldwide and one of the leading causes of disability.1 The blockade or the rupture of a blood vessel to the brain leads to either ischemic or hemorrhagic stroke, respectively.2,3 The extent and the location of the damaged brain tissue may be associated with irreversible cognitive impairment or decline in speech, comprehension, memory, and partial or total physical paralysis.4

Four chronological phases, namely hyperacute, acute, subacute, and chronic, describe the strokes cellular manifestations.5 The hyperacute phase is immediate and associated with glutamate-mediated excitotoxicity and a progressive neuronal death that can last a few hours.6 The glutamate, a potent excitatory neurotransmitter, is also an inducer of neurodegeneration following stroke.7 The acute phase, which could last over a week after the stroke, is associated with the delayed and progressive neuronal death and the infiltration of immune cells.5 The following subacute phase can extend up to three months after the stroke and is mainly associated with reduced inflammation and increased plasticity of neurons, astrocytes, microglia, and endothelial cells, allowing spontaneous recovery.8 In the chronic phase that follows, the plasticity of cells is reduced and only permits rehabilitation-induced recovery.5

The immediate treatments differ for ischemic and hemorrhagic strokes. Immediate intervention is required to restore the blood flow to the brain following an ischemic stroke. Thrombolytic agents, such as activase (Alteplase), a recombinant tissue plasminogen activator (tPA), are commonly given intravenously to dissolve the blood clots. Other more invasive approaches, such as a thrombectomy, use stents or catheters to remove the blood clot.9 Antiplatelet agents like Aspirin, anticoagulants, blood pressure medicines, or statins are generally given to reduce the risk of recurrence. Some ischemic strokes are caused by the narrowing of the carotid artery due to the accumulation of fatty plaques; a carotid endarterectomy is performed to correct the constriction.

The treatment of a hemorrhagic stroke requires a different approach. An emergency craniotomy is usually performed to remove the blood accumulating in the brain and repair the damaged blood vessels. Accumulation of cerebrospinal fluid in brain ventricles (hydrocephalus) is also a frequent complication following a hemorrhagic stroke, which requires surgery to drain the fluid. Medications to lower blood pressure are given before surgery and to prevent further seizures.10

These immediate treatments are critical to minimize the long-term consequence of the stroke but do not address the post-stroke symptoms caused by neurodegeneration. New therapeutic approaches adapted to the physiology of each phase of the stroke are currently developed. A promising therapy has been the use of stem cells.11 In this review, different clinical trials involving the use of various stem cells for the treatment of stroke are presented and compared using a meta-analysis of the published results.

To narrow down the relevant literature, a search strategy focused on original literature and reporting the clinical application of stem cells in stroke was established. An NCBI PubMed word search for stroke, stem cells, and adult stem cells yielded 146 clinical studies between 2010 and 2021. Finally, 11 studies, using autologous adult stem cells in the treatment of stroke, were considered. A PRISMA flow diagram detailing an overview of the study selection procedure and the inclusion and exclusion of papers is included in Appendix I. The inclusion criteria comprise the injection of autologous adult stem cells at any stroke stages (hyperacute, acute, sub-acute, chronic), and clinical trials whose results have been published in the last 11 years. The exclusion criteria include studies published more than 11 years ago, studies not published in English, all preclinical studies, other diseases related to stroke (ex. cardiovascular diseases), embryonic or induced pluripotent stem cells, allogeneic stem cells, and other cell therapies. Two independent researchers reviewed and filtered the 146 studies by reading the titles and abstracts. All three authors approved the final selected studies.

Stem cells are undifferentiated and unspecialized cells characterized by their ability to self-renew and their potential to differentiate into specialized cell types.12 Ischemic stroke causes severe damage to the brain cells by destroying the heterogeneous cell population and neuronal connections along with vascular systems. The regenerative potential of several types of stem cells like embryonic stem cells, neural stem cells, adult stem cells (mesenchymal stem cells), and induced pluripotent stem cells have been assessed for treating stroke.

Adult stem cells exhibit multipotency and the ability to self-renew and differentiate into specialized cell types. They have been widely used in clinical trials and a safe option thus far in treating various diseases.12,13,14 The plasticity of these cells allow their differentiation across tissue lineages when exposed to defined cell culture conditions.15 There are multiple easily accessible sources of adult stem cells, mainly the bone marrow, blood, and adipose tissue. In clinical settings, both autologous and HLA-matched allogeneic cells have been transplanted and are deemed to be safe.

Adult stem cells can secrete a variety of bioactive substances into the injured brain following a stroke in the form of paracrine signals.1618 The paracrine signals include growth factors, trophic factors, and extracellular vesicles, which may be associated with enhanced neurogenesis, angiogenesis, and synaptogenesis (Figure 1). Also, mesenchymal stem cells (MSCs) are thought to contribute to the resolution of the stroke by attenuating inflammation,19 reducing scar thickness, enhancing autophagy, normalizing microenvironmental and metabolic profiles and possibly replacing damaged cells.20

Figure 1 Schematic depicting the clinical application of different cells in stroke patients. The cells were delivered in one of three ways, intravenously, intra-arterially, or via stereotactic injections. Once administered, the cells play a role in providing paracrine signals and growth factors to facilitate angiogenesis and cell regeneration, immunomodulatory effects that serve to protect the neurons from further damage caused by inflammation, and finally, trans-differentiation of stem cells. Data from Dabrowska S, Andrzejewska A, Lukomska B, Janowski M.19 Created with BioRender.com.

A few routes of administration have been used to deliver the stem cells to the patients. The most common is through intravenous injection. Intra-arterial delivery is also performed; but this mode can be extremely painful to patients compared to an intravenous transfusion. The third approach is via stereotactic injections. This is an invasive surgery that involves injecting the cells directly into the site of affected in the brain.

Also known as mesenchymal stromal cells or medicinal signaling cells, MSCs can be derived from different sources including bone marrow, peripheral blood, lungs, heart, skeletal muscle, adipose tissue, dental pulp, dermis, umbilical cord, placenta, amniotic fluid membrane and many more.21 MSCs are characterized by positive cell surface markers, including Stro-1, CD19, CD44, CD90, CD105, CD106, CD146, and CD166. The cells are also CD14, CD34, and CD45 negative.22,23 The cells are thought to provide a niche to stem cells in normal tissue and releases paracrine factors that promote neurogenesis (Figure 2).19,20,24 During the acute and subacute stage of stroke, MSCs may inhibit inflammation, thus, reducing the incidence of debilitating damage and symptoms that may occur post-stroke.

Figure 2 Schematic describing the role of mesenchymal stem cells in stroke. The cells release different growth factors, signals, and cytokines that serve to facilitate various functions. Through the release of cytokines, they can modulate inflammation and block apoptosis. The growth factors aid in promoting angiogenesis and neurogenesis. Data from Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E.23 Created with BioRender.com.

Derived from the bone marrow, mononuclear cells contain several types of stem cells, including mesenchymal stem cells and hematopoietic progenitor cells that give rise to hematopoietic stem cells and various other differentiated cells. They can produce and secrete multiple growth factors and cytokines. They are also attracted to the lesion or damage site where they can accelerate angiogenesis and promote repair endogenously through the proliferation of the hosts neural stem cells. Mononuclear cells have also demonstrated the ability to decrease neurodegeneration, modulate inflammation, and prevent apoptosis in animal models.25,26

Blood stem cells are a small number of bone marrow stem cells that have been mobilized into the blood by hematopoietic growth factors, which regulate the differentiation and proliferation of cells. They are increasingly used in cell therapies, most recently for the regeneration of non-hematopoietic tissue, including neurons. Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used as a stimulator of hematopoiesis, which in turn amplifies the yield of peripheral blood stem cells.27

The literature review considered 11 clinical trials that satisfied the inclusion criteria. A total of 368 patients were enrolled including 179 patients treated with various types of adult stem cells. The clinical trial number 7 contained a historical control of 59 patients included in the data analysis (Figure 3). The analysis was done on the published clinical and functional outcomes of various tests such as mRS, and mBI. The analysis compared the patients clinical outcomes post stem cell therapy to the baseline clinical results. The variance in the patient population should be noted.

Figure 3 Schematic representing an overview of the total number of patients enrolled in all 11 clinical trials and the number of patients administered with each type of adult stem cell.

Abbreviations: MSC, mesenchymal stem cells; PBSC, peripheral blood stem cells; MNC, mononuclear stem cells; ADSVF, adipose derived stromal vascular fraction; ALD401, aldehyde dehydrogenase-bright stem cells.

Meta-analyses were conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. In the clinical trials, mRS and BI scores are commonly used scales to assess functional outcome in stroke patients. The BI score was developed to measures the patients performance in 10 activities of daily life from self-care to mobility. An mRS score follows a similar outcome but measures the patients independence in daily tasks rather than performance. OpenMeta[Analyst], an open-source meta-analysis software, was used to produce random-effects meta-analyses and create the forest plots. The number of patients, mean, and standard deviation (SD) of the scores were calculated to determine the study weights and create the forest plots.

All 11 clinical trials were compared based on their clinical and functional outcomes (Table 1; Figure 4). The data shows that stem cell therapy is relatively safe and viable in the treatment of stroke, indicating an improvement in patients overall health. However, when compared to the control, the improvement is not significant as patients in the control group also exhibited an improved clinical and functional outcome. Across trials that assigned a control group, the patients either received a placebo, or alternative form of treatment including physiotherapy. Variance in functional and clinical tests used to assess patients, and the number of patients enrolled in each trial results in a discrepancy in reporting. Most of the trials failed to report whether the patients suffered from an acute, subacute or chronic stroke which also affects the results of the treatments, with acute and subacute being the optimal periods to receive treatment due to cell plasticity and inhibiting unwarranted inflammation.39 The deaths in both the treatment and control population were attributed to the progression of the disease and are likely not the result of the treatment. Albeit, it has been noted down as they had occurred during the follow-up period.

Table 1 Overview of Selected Clinical Trials

Figure 4 Overview of clinical outcomes of the 11 clinical trials (N=368). (A) The chart shows the percentages of patients who have either improved, remained stable, deteriorated, or deceased. Some clinical trials are without a control arm. (B) The plot shows the overall percentage of patients that have improved after receiving either the stem cell treatment versus the standard of care. (C) The plot shows the overall percentage of patients that have remained stable and showed no clinical or functional improvement in the follow up period. (D) The plot shows the overall percentage of the patients whose condition has deteriorated in the follow up period.

A meta-analysis was conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. The results of the mRS scores were analyzed (Figure 5A; Table 2). In terms of study weights, CT6 is the highest (40.07%) as shown in Table 2. The combined results of the mRS functional test from CT1, CT5, CT6, and CT11 show a non-significant statistical heterogeneity in the studies (p-value 0.113). In conjunction, BI scores were analyzed and a meta-analysis was conducted using four comparable trials (Figure 5B; Table 3). In terms of study weights, CT3 is the highest (32.384%) as shown in Table 3. The combined results of BI scores from CT5, CT3, CT10, and CT11 show a statistical heterogeneity in the results of the studies (p-value 0.004) thus, precision of results is uncertain. More comparable studies are needed to have a better outcome. Therefore, standardized testing in trails should be considered in future trials.

Table 2 Clinical Outcomes of mRS Test

Table 3 Clinical Outcomes of BI Test

Figure 5 Meta-analysis conducted using three comparable trials. (A) Meta-analysis conducted using four comparable trials (CT1, CT5, CT6, CT11) for the mRS test. (B) Meta-analysis conducted using four comparable trials (CT3, CT5, CT10, and CT11) for the BI test.

Across all trials, patients injected with the MSCs, and other cell types did not trigger a degradation of the patient conditions demonstrating the safety of the procedures. However, the efficacy of the use of adult stem cells is less clear when compared to patients in the control group. This discrepancy could, however, exhibit improvement in patients receiving the treatment compared to the baseline clinical outcomes. However, when therapy results are compared to the patients in the control population that either received a placebo, physiotherapy, or prescribed medication, the efficacy of the use of adult stem cells is less clear.

Although multiple adult stem cell types have been used, mesenchymal stem cells have been widely used in many clinical trials. Albeit there is a consensus that the therapeutic and clinical outcomes of mesenchymal stem cell treatments are not yet significantly effective compared to the control treatment. Some trials have shown patient improvements, such as CT6 and CT8, where the investigators used PBSCs or BMMNSC, respectively. Although subjectively, the cells appear to be therapeutic, objectively, there are many limitations to the study designs included in this review. Not all the trials enrolled a control arm for a better comparison as some were only testing safety rather than efficacy. Therefore, we cannot conclude whether autologous adult stem cells are an effective therapeutic stroke treatment. Only autologous cells were included in this review as they are non-immunogenic.

Another factor to consider is the evident discrepancy in the number of patients enrolled in each trial. The trials included in this review are in Phase I and II trials, which primarily focus on safety rather than efficacy. Intravenous injection was the most used method of cell delivery due to its convenience and safety. However, it is commonly considered that this approach is not the most effective way of delivery, as the majority of the transplanted cells get absorbed by non-targeted organs, and the remaining cells find difficulty passing the blood-brain barrier. Due to this dilemma, the most obvious approach would be to inject the cells directly into the brain. However, a stereotactic procedure is invasive and will require general anesthesia, which may compromise patients health, especially ones suffering from acute ischemic stroke.40 Thus, an intra-arterial delivery seems feasible to accomplish the task as it is less invasive and might be more effective than an intravenous treatment such as the cases observed in CT3 and CT8. In CT11, the patients demonstrated a visible fmRI recovery as well as recovery of motor function in patients that have received a stem cell treatment. However, the analysis and test scores show no significance between the treatment group and the control group.

Only a few studies were comparable using a similar evaluation approach. Considering these factors, better study designs enrolling a higher number of patients in randomized clinical trial against the standard of care are needed. Moreover, a better grouping of the patients based on the type and stage of stroke may provide more relevant information for the safety and efficacy of adult stem cells for the recovery and prevention of recurrence of stroke patients.

ADSVF, Adipose-derived stromal vascular fraction; ASCs, Adult stem cells; ALD-401, Aldehyde dehydrogenase 401; BI, Barthel Index; BM-MNC, Bone marrow-derived mononuclear cells; FLAIR, Fluid attenuated inversion recovery; fMRI, Functional magnetic resonance imaging; G-CSF, Granulocyte colony-stimulating factor; MRI, Magnetic resonance imaging; MSCs, Mesenchymal stem cells; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; PBSC, Peripheral blood stem cells; SD, Standard deviation; tPA, tissue plasminogen activator.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

There is no funding to report.

We declare there is no conflict of interest.

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Autologous Adult Stem Cells in the Treatment of Stroke | SCCAA - Dove Medical Press

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Steven Fisher is a modern-day Spartan.59, 225 pounds of pure muscle, and hes constantly exercising.

In fact, his favorite hobby is touring the country, competing in Spartan Races with his wife. If youve never heard of a Spartan Race, its essentially running miles and miles, and youre rewarded for your efforts by completing physical tasks, like doing a billion pull-ups, or crawling through mud, at each mile.

For these obstacle and endurance races, youve got to be in pretty good shape.

However, as of late Fisher has had to take a break from said races. Not because hes tired, or anything like that. The mans a machine. His hiatus has stemmed from a life-long nagging injury thats been flaring up.

He said it all started during his young and dumb days. He and his friends were tobogganing down a hill. Fisher, who was 20 at the time, said he stood up on the toboggan to attempt a little surfing. He felt like a regular Kelly Slater before falling backwards.

Learn more:Orthopedics regenerative medicine at Sanford Health

My elbow hit into the ground and just caught. I broke my humerus into three pieces. Obviously, that was a lot of trauma in my shoulder as well, Fisher said.

Because of the impact, his doctor told him he was lucky his humerus didnt shoot through his shoulder.

Normally thats what they see with that kind of fall.

He went through rehabilitation, and other than some trouble resting his hands behind his head, he said he made a full recovery.

Fast forward a few decades, and hes lifting weights, running Spartan Races, and seemed to be doing well. One day, though, he noticed a sharp pain in the same shoulder he injured as a young adult.

He said he couldnt heal it the ways he normally would. So, he went to his doctor.

He said I had arthritis. At the age of 43. He said if I was older, wed be talking about replacing my shoulder, he said.

Fisher got aPRP, or platelet rich plasma, injection. He noticed some relief for eight months, before the pain returned.

Basically at that point it was a labrum tear, and Id been re-tearing it quite a bit, Fisher said. He got another PRP shot but started to look more into stem cells and regenerative medicine. He lives in West Virgina and found a few doctors who offer stem cell therapy.

But you cant find a lot of information on how they do it, like what their method is. They dont even say if its from bone marrow or from fat. They also dont tell you how theyre extracting the stem cells, like if its mechanical or theyre doing something else. Theyre not going to tell you that stuff, he said.

He wanted to continue to explore this form of treatment, but only if it was done the right way. He talked with multiple providers on the East Coast, but it just didnt feel right.

Then, he stumbled onto Sanford.

He said he started talking with Tiffany Facile, the clinical director of regenerative medicine at Sanford Health. She explained to him that the stem cell treatment, and ENDURE clinical trial,Sanford Healthcan offer might be a great fit for Fisher.

We talked about different studies, and we talked about what Sanford is doing. Shes obviously really excited about it and there were some previous studies (Sanford has) done. I read up on the previous studies, and the results on the previous studies. For example, with a rotator cuff, they had done the same process and got great results with it, Fisher explained.

He also said he truly felt like he was heard and understood at Sanford Health. Some of the other places felt like more of a shop, so to speak, he said.

Everybody, from the top down to even the front desk, they were gracious. Everybody Ive worked with, theyre all passionate about this. I never felt like I was just getting pulled along, and I didnt have a say in my care or anything like that. I felt I was more part of the process itself and like I was walking with them, he said.

Fisher received adipose-derived stem cell treatment from Sanford. He said the way Sanford Health delivered the treatment differs from other health care providers. He explained some providers use a mechanical method to extract the stem cells, but Sanford uses a more concentrated enzyme-derived method.

There is an estimated range on the amount of stem cells that get extracted, like from an enzyme approach versus mechanical, and it can be on the order of like a thousand times more cells going to be extracted, versus the mechanical, he said.

Hes still on the sidelines for Spartan Races, but hes hoping to get back on the course soon. He has a check-up in January, but he says he feels both physically and mentally better after receiving care from Sanford.

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Cell therapy helps Sanford patient get back to racecourse - Sanford Health News

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By Stephanie Banat

17-year-old Samantha Horowitz is teaching the world about the healing powers of music.

A lifelong Merrick resident, Horowitz is a senior at Calhoun High School who for the past three years has been the sole vocalist in the production of a musical documentary, Second Chance, based on her mother, Tara Notricas, long battle with mast cell disease.

Some of the songs were written from my perspective, and some were written from my moms perspective, Horowitz explained. Music has given us the freedom to express things that we couldnt put into words and I truly believe its a huge part of the reason that my mom is here with us today.

In honor of her creative, healing effort, the Herald is proud to name Horowitz its 2021 Person of the Year.

Since Notricas early 20s, she had suffered from a number of physical maladies of unknown causes, including episodes of anaphylactic shock, hair loss and other issues.

It wasnt until April 2011, after consultations with scores of specialists, that Notrica was finally diagnosed with mast cell activation syndrome, a rare disorder caused by abnormal or overly active mast cells that affects multiple organ systems, including the gastrointestinal, neurological, endocrine, cardiac and respiratory systems.

It took a huge toll on me and my family, Horowitz said. I was 5 at the time, and I didnt understand what was going on. I just knew that my mom was sick, and that she couldnt be the mom she wanted to be for my brother, Jared, and I.

In 2018, Notrica endured a stem cell transplant, which was unsuccessful. Next, that June, her doctors offered her the option of receiving a bone marrow transplant, which, they said, she had a 50-50 chance of surviving. Nonetheless, Notrica decided to go forward with the procedure.

At this time, the whole music process really started picking up, her daughter said, because there were now a lot more emotions we were experiencing to write about because there were some days that my mom woke up and really didnt think she was going to make it.

Just two weeks before the bone marrow transplant, the family began filming a documentary, directed by Rochester-based filmmakers Matthew White and Brian Gerlach. The film documents Notricas health journey, and focuses on the weeks leading up to the transplant. Its title, Second Chance, comes from one of its songs, which is about Notrica getting a second chance at life, and getting to experience everything she had missed out on because of her illness.

Since 2017, Horowitz has written and recorded 11 original songs for the film. Her music career, however, started long before the documentary.

Ive had a passion for singing since I was around 3 or 4 years old, she said. In elementary school I did musical theater, and then in middle school I began writing my own original songs.

In 2017, at age 13, she wrote her first song for the documentary, alongside her mother and her vocal coach, former American Idol contestant and Merrick native Robbie Rosen. The ballad, called Brave the Storm, was written to show Notrica that she wasnt facing her illness alone, her daughter said.

Another one of her favorite songs from the documentary, Horowitz said, is called Carry On, which she wrote from her mothers perspective. This song is basically my mom saying that if it came down to it and she didnt make it, she wants my family to carry on without her, Samantha said, because shed always be a part of us and would always be watching over us.

Now, nearly three years after the transplant, and after facing a multitude of complications from it, Notrica is still under medical care at home.

The biggest thing, Horowitz said, is throughout this whole process of my mom being sick, whats always brought her a sense of comfort is music. Not just her favorite artists on the radio, but really the fact that I could sing to her and bring her joy and show her that there are things in life that are certainly worth fighting for not just her family, but also things like music.

Aside from her music, Horowitz has earned academic accolades throughout her high school career, and is a member of Calhouns national, math, science, English, social studies and world language honor societies. She is also a peer tutor for other students.

Rosen, who has gotten to know Horowitz well over the past four years, spoke about her dedication to the film and her ability to balance her various responsibilities despite the hardships shes faced. Shes been through so much since her childhood, Rosen said, so I think that her ability to keep it together, get the grades that she does, focus on music the way she does, and persevere through everything is a testament to who she is, her strength and her talent.

Calhoun Principal Nicole Hollings also noted Horowitzs many strengths, and the reasons that she is an ideal role model for others. Aside from being an outstanding student who has taken rigorous courses throughout high school, Hollings said, Samantha has been involved in many community service opportunities, and has always given her time and help to others who need it. She is truly a role model to others, showing how to be strong, caring, and how to live life in the moment, making every moment count, no matter how difficult it might be to do that.

Horowitz said that her mothers health journey has inspired her to major in biology when she starts college next year, and that she plans to go into the medical field. Im really interested in studying the correlation between music and someone healing, she said, Although this journey has caused me a lot of suffering, its made me extremely passionate about what I want to do with my future, and honestly, it has made me into who I am today.

Aside from sharing the familys ordeal, the documentary raises awareness of rare diseases, educates about bone marrow transplants, encourages people to become bone marrow donors and promotes State Senate Bill S1377, which would require school districts to establish medical hardship waiver policies.

But Horowitz said that her overall goal in creating the documentary is to help others who may be going through similar struggles. The main purpose isnt just to share my moms story or to get our music out there, she said, but really, its for people who are going through similar situations to see that they arent alone because its not easy for everyone to talk about their condition the way my mom does, and not everyone has a family member that can make songs about their journey to comfort them but I believe this film has the power to change peoples perspectives on life and to show them that music truly is a coping mechanism.

She added that she hoped the film would teach people not to take life for granted, and to make the best of every negative situation.

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Healing others with music - liherald

Bone Marrow Stem Cells Comments Off on Healing others with music – liherald | January 3rd, 2022

Abstract:

Over the last decade, stem cell-associated therapies are widely used because of their potential in self-renewable and multipotent differentiation ability. Stem cells have become more attractive for aesthetic uses and plastic surgery, including scar reduction, breast augmentation, facial contouring, hand rejuvenation, and anti-aging. The current preclinical and clinical studies of stem cells on aesthetic uses also showed promising outcomes. Adipose-derived stem cells are commonly used for fat grafting that demonstrated scar improvement, anti-aging, skin rejuvenation properties, etc. While stem cell-based products have yet to receive approval from the FDA for aesthetic medicine and plastic surgery. Moving forward, the review on the efficacy and potential of stem cell-based therapy for aesthetic and plastic surgery is limited. In the present review, we discuss the current status and recent advances of using stem cells for aesthetic and plastic surgery. The potential of cell-free therapy and tissue engineering in this field is also highlighted. The clinical applications, advantages, and limitations are also discussed. This review also provides further works that need to be investigated to widely apply stem cells in the clinic, especially in aesthetic and plastic contexts.

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Exploring the potential of stem cell-based therapy for aesthetic and plastic surgery - Newswise

Skin Stem Cells Comments Off on Exploring the potential of stem cell-based therapy for aesthetic and plastic surgery – Newswise | December 23rd, 2021

"We started speaking with Kieron Jones and Andrew Strong as we were funded and started to execute our R&D plan, and the rest is history. We appreciate the variety of support services K2bio offers in addition to rental lab space," stated Kevin Slawin, CEO of Ponce Therapeutics. Ponce Therapeutics was the first client to enter into a contract with K2bio.

"We are very excited to welcome Ponce Therapeutics to the K2bio family," said Kieron Jones, Co-founder, CEO, and President of K2bio. "Our goal is to build a collaborative environment That allows companies within our facility to focus on efficiently developing their product. For companies outside of our facility, we offer a suite of contracted services to support their in-vivo and in-vitro needs as a long-term partner built on quality and timeliness."

About K2bio K2bio is a state-of-the-art facility with a unique model of providing preclinical contract research services and an incubator environment. We provide a unique and flexible co-working facility for high-potential, early-stage life science companies, with experienced biotech research managers and staff, in addition to a mouse vivarium to allow companies access to the research environment that they need to progress at an affordable cost. We've created the concierge of biolabs, offering researchers the option to add or subtract services based on their individual needs.

For more information, visit https://K2-biolabs.com.

About Ponce Therapeutics - Ponce Therapeutics is currently developing a biotechnology platform to restore young cells in the skin, targeting p16-expressing senescent cells for elimination. While initially focused on skin, Ponce plans to develop a wide-ranging portfolio of anti-aging products, which could ultimately lead to new cancer treatments. The elimination of pro-inflammatory senescent cells has been shown to suppress cancer and rejuvenate tissues by restoring stem cell niches to their healthy state. Ponce is headquartered in Miami, Florida, with research facilities located in Houston, TX.

For more information, visit https://poncetherapeutics.com.

SOURCE K2bio

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K2bio Welcomes Ponce Therapeutics to Houston - PRNewswire

Skin Stem Cells Comments Off on K2bio Welcomes Ponce Therapeutics to Houston – PRNewswire | December 23rd, 2021

Our cells are packed with unrealized potential. Almost every human cell contains the genetic information it needs to become any other kind of cell. A skin cell, for example, has the same genes as a muscle cell or a brain neuron, but in each type of cell only some of those genes are switched on, while others remain silent. Its a little like making different meals out of the same ingredients cupboard. If we understand the recipe behind each type of cell, then theoretically we can use this information to engineer every single cell type in the human body.

That is Mark Kotters goal. Kotter is the CEO and cofounder of bit.bioa Cambridge, UK, based company that wants to revolutionize clinical research and drug discovery by producing precisely engineered batches of human cells. Basic scientific research into new drugs and treatments often starts with tests in mice, or in the most widely used human cell lines: kidney cells and cervical cancer cells. This can be a problem, because the cells being experimented on may have major differences to the cells that a candidate drug is supposed to target in the human body. A drug that works in a mouse may turn out not to work when it's tested in humans. There is no mouse on this planet that has ever suffered from Alzheimers, it just doesnt exist, Kotter says. But testing a potential Alzheimers drug on a human brain cell engineered to have signs of Alzheimers disease could give a much clearer indication of whether that drug is likely to be successful.

Every cell type has its own little program, or postcodea combination of transcription factors that defines it, says Kotter. By inserting the right program into a stem cell, researchers can activate genes that code for these transcription factors and turn a stem cell into a specific type of mature cell. Unfortunately, biology has a way of fighting back. Cells often silence these genes, stopping the transcription factors from being produced. Kotters solutiondiscovered as part of his research at the University of Cambridgeis to insert this program in a region of the genome thats protected against gene silencing, something Kotter refers to as a genetic safe harbor.

Bit.bio currently sells two different reprogrammed cell lines: muscle cells and a specific kind of brain neuron, but the plan is to create bespoke cell lines for use in the pharmaceutical industry and academic research. What were doing with our partners in the industry now is to create genetic modifications that are relevant for diseases, Kotter says. He compares this approach to running software on a computer. By inserting the right bit of code into a cells genome, you can control how that cell behaves. That means that we can now run programs, and we can reprogram human cells, Kotter says. The cell reprogramming technology could also go well beyond model cell lines and help develop whole new kinds of treatment, such as cell therapy.

In some cell therapies, a patients own immune cells are grown outside of their body before being modified and inserted back into it to help fight a diseasea long and expensive process. One kind of cell therapy used to treat young people with leukemia costs more than 280,000 ($371,400) per patient. Bit.bios chief medical officer Ramy Ibrahim says that the firms technology could help drive down the cost of cell therapy and make it easier to manufacture immune cells at a large scale. Having abundant numbers of the right cell types that we can now make edits to, I think will be transformational, he says.

More Great WIRED Stories

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This Startup Is Makingand ProgrammingHuman Cells - Wired.co.uk

Skin Stem Cells Comments Off on This Startup Is Makingand ProgrammingHuman Cells – Wired.co.uk | December 23rd, 2021

I first dismissed this as a fancy version of those old heat patches you can get in the chemist, but I couldnt have been more wrong. Embedded within the lightweight but stretchy plaster-type fabric is enough clove and safflower to help get your blood flowing, as well as borneol to reduce inflammation and pain. And they really work.

15, available at Victoriahealth.com.

Jones Road The Best Pencil in Ultra Opaque

You cant go wrong with this one-style-fits-all eye pencil from make-up maverick Bobbi Browns newest cosmetic venture, which can outline, graphic line, feline line, smoky smudge line, whatever you choose. Point it at your lids and it pretty much does the rest by itself, its the very definition of fuss-free for those who dont like to overthink their eyeliner.

20, available at Jonesroadbeauty.com.

Ffern Organic Seasonal Fragrance

This is as small batch and as sustainable as it gets. Its also highly exclusive as you have to sign up for each new-season limited-edition release. But youll be happy you did, with each perfume created by master perfumer Francois Robert and his protg Elodie Durande, and delivered in entirely sustainable packaging. My favourite this year was Spring 2021, which had top notes of ginger underpinned by neroli, jasmine sambac absolute and orange absolute.

Available at Ffern.co.

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The 37 Best Beauty Products Of 2021 - British Vogue

Skin Stem Cells Comments Off on The 37 Best Beauty Products Of 2021 – British Vogue | December 23rd, 2021

The question really, is what should you be using retinol with. Hydrating ingredients like glycerin, peptides, ceramides, when sandwiched with your retinol, all help to support the integrity of the skin.

Ultimately, you should listen to your skin and let it be your guide. Ayodele advises keeping a diary noting any changes and taking pictures of your skin, comparing week one to week six. And remember: it is crucial to use SPF every day with retinol.

From the best formula for dark spots to products that are perfect for mature skins, heres Vogues edit of the best retinol creams and serums to try now:

The Best Retinol For Sensitive Skin: La Roche-Posay Retinol 0.3% + Vitamin B3 Serum

La Roche Posay - Retinol B3

La Roche Posay via Marionnaud.fr

La Roche-Posay knows its way around an excellent skincare product this serum is just one among many. Combining vitamin B3 with 0.3 per cent retinol, its a gentle one, and good for even the most sensitive skins.

Best Affordable Retinol: The Ordinary Granactive Retinoid 2% in Squalane

The Ordinary - mulsion de Granactive Retinoid* 2%

The Ordinary via Nocibe.fr

The Ordinary is renowned for bringing us premium ingredients at affordable prices, and this product comes in at well under 10. High potency, minimal irritation, low price whats not to love?

Retinol for Beginners: REN's Organic Retinoid Youth Serum for Sensitive Skin.

REN - Srum Jeunesse Bio Retinoid

Concerned about dryness and irritation? This REN formula is suitable for even the most sensitive skin, especially those that have previously reacted to retinol. The formula's unique delivery system allows for effective cell renewal without causing irritation.

Best Retinol Serum: Institut Esthederm Intensive Retinol Face Serum

Institut Esthederm - Intensive Retinol

6347

Institut Esthederm via Nocibe.fr

Perfect for deep-set wrinkles, this emollient-rich retinol serum effectively locks in moisture while working hard to bring plumpness back to the most sullen skin.

Best Retinol Booster: Paulas Choice 1% Retinol Booster

Paula's Choice - Boost Retinol 1%

Paula's Choice via Amazon.fr

Designed to be added to your favourite serum or moisturiser, Paulas Choice 1% Retinol Booster offers a more customisable approach to retinol use, making it perfect for beginners.

Best Retinol Overnight Mask: Allies of Skin 1A Retinal and Peptides Overnight Mask

Allies of Skin - 1A Retinal + Peptides Overnight Mask

Allies of Skin via Galerieslafayette.com

This antioxidant-rich formula delivers a jolt of nourishment to thirsty mature skin. Fortified with Ally-R, an encapsulated form of time-release retinaldehyde (a vitamin A even more powerful than retinol), this moisture barrier-maintaining formula helps promote firmness and smoothness in lacklustre skin.

Best Retinol For Acne: Lixir Night Switch Retinol 1%

Lixir Skin - Srum pour le visage Night Switch Retinol 1%

Lixir Skin via Net-a-porter.com

Lixirs Night Switch range is based on the idea that using too many active ingredients at once can confuse the skin. Instead, it advocates the frequent switching up of products. Night Switch Retinol 1% refines skin texture and boosts plumpness and firmness.

The most nourishing: Ideal Resource Youth Oil Concentrate with retinol by Darphin

Darphin - Ideal Resource Concentr huile jeunesse au retinol

9063

Darphin via Marionnaud.fr

Thanks to micro-encapsulated retinol, these mini-doses accelerate cell renewal and reinforce collagen production, helping to fight the signs of aging. Each one also contains a blend of plant oils that nourish the face and plump the eye area.

Fastest results: Este Lauder Perfectionist Pro

Este Lauder - Perfectionist Pro

12090

Este Lauder via Marionnaud.fr

Only 28 days to see visible results on the skin: that's the promise of this express treatment by Este Lauder. The result is smoother, softer, supple skin and a more radiant complexion. A must-have.

The best face cream: A-Passioni Retinol Cream by Drunk Elephant

Drunk Elephant - Crme A-Passioni Retinol

Drunk Elephant via Cultbeauty.com

Specially designed for sun-damaged skin, this cream combines 1% retinol with a cocktail of fruit extracts such as passion fruit, apricot and winter cherry to reduce the appearance of fine lines and deep wrinkles.

The Best Retinol Cream Available Over The Counter: SkinCeuticals Retinol 0.3% Cream

SkinCeuticals - Retinol 0.3 Peeling De Nuit Rides & Imperfections

SkinCeuticals via Nocibe.fr

The SkinCeuticals formula utilises encapsulation technology, to minimise irritation and allow the chamomile-derived bisabolol to counter any that does occur.

Best Retinol Night Oil: Sunday Riley Luna Sleeping Night Oil

Luna - Huile de nuit Sunday Riley

Luna via Cultbeauty.com

Sunday Rileys bestselling Luna Sleeping Night Oil combines retinoid oil with blue tansy and cold-pressed chia, grape seed and avocado oils to renew the skins surface overnight. A celebrity favourite.

Best Retinol For Wrinkles: Elizabeth Arden Retinol Ceramide Capsules Line Erasing Night Serum

Elizabeth Arden - Retinol Ceramide Capsules

5340

Elizabeth Arden via Marionnaud.fr

By combining retinol with skin-loving ceramides, Elizabeth Arden allows you to swerve any flaking. The capsule format means you wont apply too much, and also keeps the formula fresh.

Best Retinol For Dullness: Medik8 R-Retinoate Intense

Medik8 - Crme rajeunissante intense r-Retinoate

Medik8 via Net-a-porter.com

Suffering from dull skin? Look no further than Medik8s ultimate time-defying treatment. Combining retinol with clinical-strength retinoic acid, as well as nourishing peptides, ceramides, and hyaluronic acid, this miracle cream works overnight to plump and smooth the skin, firming it up and leaving it brighter and more replenished.

Best Retinol For Mature Skin: LOral Paris Pure Retinol Revitalift Laser Night Serum

L'Oral - Revitalift Laser Srum Nuit Rtinol Pur

For those in need of some extra TLC, LOrals powerhouse serum is formulated with a high concentration of pure retinol. One of the brands most potent blends, it targets fine lines and wrinkles, while added hyaluronic acid replenishes the skin with moisture.

Best Retinol Alternative: The Inkey List Bakuchiol Moisturiser

The Inkey List - Bakuchiol Moisturiser

The Inkey List via Cultbeauty.com

If youre finding retinol too harsh, there is a gentler alternative: bakuchiol, a plant-based super ingredient. Powered by bakuchiol, this moisturiser works to reduce the appearance of fine lines and wrinkles and smooths uneven skin, without causing irritation. Meanwhile added squalane, glycerin and sach inchi oil provide hydration and nourishment.

Best Retinol For Brightening: StriVectin Super-C Retinol Brighten & Correct Vitamin C Serum

Strivectin - Super-C Retinol Srum Illuminateur & Correcteur Vitamine C

Strivectin via 1001pharmacies.com

With two hardworking actives vitamin C and retinol this lightweight serum is a multi-tasking wonder. Expect it to brighten, smooth, ease fine lines and strengthen the skin barrier, too.

Best Retinol For Tackling Signs Of Ageing: Sarah Chapman Skinesis Retinol Oil

Combining plant stem cells, platinum peptide delivery and time-release retinol, Sarah Chapmans Skinesis Platinum Stem Cell Elixir is a true super serum, acting on fine lines and wrinkles, increasing collagen synthesis, and improving skin elasticity.

Available at Lookfantastic.com.

Best Retinol For Wrinkles: Murad Retinol Youth Renewal Serum

Murad Cosmetic - Resurgence Renewing Eye Cream

Murad Cosmetic via Nocibe.fr

With clever three-part retinol technology, which comprises a fast-acting retinoid, a time-released retinol and a retinol booster, expect uneven texture (and the like) to be addressed from all angles with the help of this Murad serum.

The best night cream with retinol: Lancme Corrective Night Concentrate

Lancme - Concentr nuit correcteur

Lancme via Galerieslafayette.com

A powerful treatment, rich in retinol, vitamin A and hyaluronic acid, which moisturizes and firms the skin while reducing the appearance of wrinkles. However, we recommend avoiding it if you have sensitive skin.

This article was previously published on Vogue.co.uk

Original post:
20 of the best retinol creams & serums for every skin type - VOGUE Paris

Skin Stem Cells Comments Off on 20 of the best retinol creams & serums for every skin type – VOGUE Paris | December 23rd, 2021

DUBLIN--(BUSINESS WIRE)--The "Global Regenerative Medicine Market Size, Share & Trends Analysis Report by Product (Cell-based Immunotherapies, Gene Therapies), by Therapeutic Category (Cardiovascular, Oncology), and Segment Forecasts, 2021-2027" report has been added to ResearchAndMarkets.com's offering.

The global regenerative medicine market size is expected to reach USD 57.08 billion by 2027, growing at a CAGR of 11.27% over the forecast period.

Recent advancements in biological therapies have resulted in a gradual shift in preference toward personalized medicinal strategies over the conventional treatment approach. This has resulted in rising R&D activities in the regenerative medicine arena for the development of novel regenerative therapies.

Furthermore, advancements in cell biology, genomics research, and gene-editing technology are anticipated to fuel the growth of the industry. Stem cell-based regenerative therapies are in clinical trials, which may help restore damaged specialized cells in many serious and fatal diseases, such as cancer, Alzheimer's, neurodegenerative diseases, and spinal cord injuries.

For instance, various research institutes have adopted Human Embryonic Stem Cells (hESCs) to develop a treatment for Age-related Macular Degeneration (AMD).

Constant advancements in molecular medicines have led to the development of gene-based therapy, which utilizes targeted delivery of DNA as a medicine to fight against various disorders.

Gene therapy developments are high in oncology due to the rising prevalence and genetically driven pathophysiology of cancer. The steady commercial success of gene therapies is expected to accelerate the growth of the global market over the forecast period.

Regenerative Medicine Market Report Highlights

Key Topics Covered:

Market Variables, Trends, & Scope

Competitive Analysis

Covid-19 Impact Analysis

Regenerative Medicine Market: Product Business Analysis

Regenerative Medicine Market: Therapeutic Category Business Analysis

Regenerative Medicine Market: Regional Business Analysis

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/kovhgl

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Global Regenerative Medicine Market is Expected to Reach USD 57.08 Billion by 2027, Growing at a CAGR of 11.27% Over the Forecast Period. -...

Spinal Cord Stem Cells Comments Off on Global Regenerative Medicine Market is Expected to Reach USD 57.08 Billion by 2027, Growing at a CAGR of 11.27% Over the Forecast Period. -… | December 23rd, 2021

Image by MasterTux from Pixabay

The brain is the most complex thing in the universe! It is made up of an intricate network of cells called neurons. Neurons are long, elongated, fibre-like cells, and billions of them form a complex network of connections called synapses. Neurons are not physically connected, but they transmit messages between them electrochemically as non-contact nerve impulses. And, there are trillions of such connections in our brain. However, in the initial stages, when the embryo is developing, the primitive neurons are rounded and lack connection to each other.

So how do these innocuous-looking rounded cells become highly connected elongated neurons? Researchers from Manipal Institute of Regenerative Medicine, Bengaluru, found the key gene that assists in making this happen. The study published in iScience journal shows that a gene called Superoxide dismutase 2 (SOD2), hitherto known to be involved in another function, is caught performing a completely different function -- promoting the generation of neurons. The authors state that although a complete understanding of the exact mechanism of how this happens remains to be unravelled, there is a possibility that one day, human nerve cells could be grown from any human tissue cells, thereby opening therapeutic avenues for patients with nerve or spinal cord injuries.

Existing literature indicates that SOD2 basically mops oxygen radicals inside the cell. During normal metabolism, cell components called mitochondria generate energy-rich molecules from carbon sources. However, the process produces an undesirable byproduct called oxygen radicals. These are oxygen molecules with an extra electron on them which makes them highly reactive with other molecules, thereby causing toxicity in the cells. The usually designated job of the SOD2 gene is to minimise this damage by mopping up these free oxygen radicals. The researchers found that the SOD2 mop had another function: to help the cells become neural precursors, which in turn become highly connected neurons. The process is termed Differentiation.

Scientists differentiate a neuron cell from an embryonic cell by its shape and by looking for specific proteins produced only in these neuronal cells. These proteins are markers for that particular cell type.

To decipher SOD2s role in the differentiation process, the researchers introduced copies of the SOD2 gene into mouse embryonic stem cells grown in the lab (cultured cells). When they increased the number of copies of the gene, the embryonic cells changed into a neuron-like appearance and exhibited markers unique to cells of neurons. However, the markers were absent when they eliminated the SOD2 gene.

In our study, using embryonic cells, we show that when SOD2 is knocked down or eliminated and subjected to differentiation, the embryonic cells could not specifically change into a neuron. However, this did not compromise the differentiation to other tissues, says Dr Anujith Kumar, corresponding author of the paper.

Owing to numerous ethical problems associated with procuring human embryonic cells, the researchers used fibroblasts or skin cells of mice and intended to convert them into stem cells that mimic embryonic cells. They achieved this by introducing another gene called OCT4 into the fibroblast cells. When the researchers transferred the SOD2 gene and OCT4, fibroblasts stopped being fibroblasts and changed into neurons, but not pluripotent stem cells. (Pluripotent stem cells are master cells that can differentiate into almost any tissue cell type).

So how does SOD2 actually do this? The researchers hypothesised that SOD2 could be having other functions that involved mitochondria. However, they had to first observe the microscopic mitochondria inside the cell to test their hypothesis. To do so, they tagged a protein found on the mitochondrial surface with a fluorescent dye. Under a fluorescent microscope, these tagged mitochondria appear fluorescent. When the SOD2 gene was introduced in the cell, they could see that the mitochondria were longer than they would be. This is because the individual mitochondria had fused to produce longer filament like mitochondria.

Mitochondria fuse because of a protein called MFN2. Researchers found that the expression of SOD2 was causing the overproduction of MFN2 protein. The fusing of mitochondria was somehow related to the embryonic cells elongating and growing into neurons. But how exactly that happens is still a mystery.

Mechanistically, it is unclear how mitochondrial fusion and fission favour commitment to neuron formation, says Dr Kumar. However, he speculates that As neurons are dynamic cells and dependent on excessive energy molecule ATP (adenosine tri-phosphate), probably mitochondrial fusion favours the energy supply and in turn facilitates neural formation.

The research done on mouse cells needs to be repeated with human cells, and hopefully, the results will one day be helpful to treat nerve injuries. At this juncture, the current findings on differentiated neurons thus produced are suitable for research purposes to study neuronal development. It could also be used to develop an experimental framework to model diseases in the cells by growing them in the lab. Such experiments could be utilised for drug screening and also where researchers test the effect of promising drugs by trying them on these cells.

This article has been run past the researchers, whose work is covered, to ensure accuracy.

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Scientists unravel a gene function that helps the genesis of neurons - Research Matters

Spinal Cord Stem Cells Comments Off on Scientists unravel a gene function that helps the genesis of neurons – Research Matters | December 23rd, 2021