Introduction

The skin is the largest organ in the body, coveringits entire external surface.The skinhas3 layersthe epidermis, dermis, and hypodermis,which have different anatomical structures and functions (seeImage.Cross Section, Layers of the Skin). The skin's structure comprises an intricate network that serves as the body's initial barrier against pathogens, ultraviolet (UV) light, chemicals, and mechanical injury.This organ also regulates temperature and the amount of water released into the environment.

Skin thicknessvariesby body region and isinfluenced by the thickness of the epidermal and dermal layers. Hairless skin in the palms of the hands and soles of the feet is the thickest due to the presence ofthe stratum lucidum, an extra layer in the epidermis.Regions lacking this extra layer are considered thin skin. Of these regions, the back has the thickest skin because it has a thick epidermis.[1][2][3]The skin's barrier function makes it susceptible to various inflammatory and infectious conditions. In addition, wound healing, sensory changes, and cosmesis are significant surgical concerns. Understanding the skin's anatomy and function is crucial for managing conditions across all medical fields.

Epidermis

The epidermis, the skin's outermost layer, is composed ofseveral strata and various cell types crucial for its function.

Layers of the epidermis:From the deepest to the most superficial, the epidermal layers are the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The stratum basale,also known asstratum germinativum, is separated from the dermis by the basement membrane (basal lamina) and attached to it by hemidesmosomes. The cells in this layer are cuboidal to columnar, mitotically active stem cells that constantly produce keratinocytes. This layer also contains melanocytes. The stratum spinosum, comprising 8to 10 cell layers, isalsocalled the prickle cell layer. This layer contains irregular, polyhedral cells with cytoplasmic processes, sometimes called spines,that extend outward and contact neighboring cells by desmosomes. Dendritic cells can be found in this layer.[4][5]

The stratum granulosum has 3to 5 cell layers and containsdiamond-shaped cells with keratohyalin and lamellar granules. Keratohyalin granules contain keratin precursors that aggregate, cross-link, and form bundles. The lamellar granules contain the glycolipids secreted to the cell surfaces, functioning as anadhesiveto maintain cellular cohesion. The stratum lucidumcomprises 2 to 3 cell layers and ispresent in thicker skin on the palms and soles. This thin and clear layer consists of eleidin, a transformation product of keratohyalin. The stratum corneum has 20to 30 cell layers and occupies the uppermost epidermal layer. The stratum corneumis composed of keratin and dead keratinocytes (anucleate squamous cells) that form horny scales. This layer has the most variable thickness, especially in callused skin. Dead keratinocytesrelease defensins within this layer, which are part of our first line of immune defense mechanisms.[6][7]

Cells of the epidermis:The epidermal cells include keratinocytes, melanocytes, and Langerhans and Merkel cells(seeImage.Cells of the Epidermis). Keratinocytes are the predominant cells of the epidermis,originating from the basal layer. These cells produce keratin and lipids essentialforformingthe epidermal water barrier. Keratinocytes also contribute to calcium regulation by enablingUVB light absorption in the skin,which iscriticalfor vitamin D activation. Melanocytes derive from neural crest cells and primarilysynthesize melanin, the main skin pigment component. These cells are found between stratum basale cells. UVB light stimulates melanin secretion, protecting against further UV radiation exposure and acting as a built-in sunscreen. Melaninforms during the conversion of tyrosine to dihydroxyphenylalanine by the enzyme tyrosinase. Melanin then travels from cell to cell, relying on the long processesconnecting the melanocytes to the neighboring epidermal cells. Melanin granules from melanocytestransit through the lengthy processes to the cytoplasm of basal keratinocytes. This transfer occurs through cytocrine secretion, where keratinocytes phagocytose the tips of melanocyte processes.

Langerhanscellsare dendritic cells that act as the skin's first-line cellular immune defenders andare crucialfor antigen presentation. Special stains allow visualization of these cells in the stratum spinosum. Langerhans cells are of mesenchymal origin, derived from CD34-positive bone marrow stem cells, and are part of the mononuclear phagocytic system.These cells contain Birbeck granules and tennis racket-shaped cytoplasmic organelles. Langerhans cells express major histocompatibility complex (MHC) I and MHC II molecules, uptake antigens in the skin, and transport them to the lymph nodes. Merkel cells are oval-shaped modified epidermal cells found in the stratum basale, directly above the basement membrane. These cells serve as mechanoreceptors for light touch and are found in the palms, soles, and oral and genital mucosa, with the highest concentration in the fingertips. Merkel cells bind toadjoining keratinocytes through desmosomes and contain intermediate keratin filaments. The cell membranes of Merkel cells interact with free nerve endings in the skin.

Dermis

The dermis is connected to the epidermisby the basement membrane.The dermis consists of 2 connective tissue layers, papillary and reticular, which merge without clear demarcation. Thepapillary layeris the upper dermal layer,which isthinner and composed of loose connective tissue that contacts the epidermis. Thereticular layeris the deeper layer, which is thicker and less cellular. This layer consists of dense connective tissuecomposedof collagen fiber bundles. The dermis houses the sweat glands, hair, hair follicles, muscles, sensory neurons, and blood vessels.

Hypodermis

The hypodermis, also known as the subcutaneous fascia, is located beneath the dermis.This layer is the deepest skin layer and contains adipose lobules,sensory neurons, blood vessels, and scanty skin appendages, such as hair follicles.

Functions

The skin's comprehensive roles highlight its complexity and importance in maintaining overall health and well-being.These roles are discussed below.[8][9]

Barrier function:The skin has multiple protective roles, acting as a barrier against various external threats. The skinshieldsthe body fromexcessive water loss or absorption, invasion by microorganisms, mechanical and chemical trauma, and UV light damage. The cell envelope establishes the epidermal water barrier, a layer of insoluble proteins on the inner surface of the plasma membrane. This barrier is formed through thecross-linkingof small proline-rich proteins. Larger proteins such as cystatin, desmoplakin, and filaggrincontribute to the barrier's robust mechanics. The lipid envelope is a hydrophobic layer attached to the outer surface of the plasma membrane. Keratinocytes in the stratum spinosum produce keratohyalin granules and lamellar bodies containing a mixture of glycosphingolipids, phospholipids, and ceramides assembled within Golgi bodies. The contents of lamellar bodies are then secreted through exocytosis into the extracellular spaces between the stratum granulosum and corneum.

Immunological defense:The skin plays a crucial role in both adaptive and innate immunity. In adaptive immunity, antigen-presenting cells initiate T-cell responses, leading to increased levels of helper T cells, such as TH1, TH2, or TH17. In innate immunity, the skin produces various peptides with antibacterial and antifungal properties. The skin-associated lymphoid tissue is a significant component of the immune system,aiding in preventing infections, as even minor skin breaks can lead to infection. Langerhans cellsare part of the adaptive immune system, presenting foreign antigens encountered in the skin to T cells.

Regulation of homeostasis:The skin plays a vital role in maintaining body temperature and water balance. This organregulates heat exchange with the environment, particularly through the blood vessels and sweat glands. The skin managesthe rate and amount of water evaporation and absorption.

Endocrine and exocrine functions:Keratinocytes produce vitamin D by converting 7-dehydrocholesterol under UV light exposure. These cells also express the vitamin D receptor and contain enzymes that activate vitamin D, essential for the proliferation and differentiation of keratinocytes. The skin's exocrine functions include temperature control by perspiration and skin protection by sebum production. Sweat and sebaceous glands are crucial to these functions.

Sensory functions:The skin is equipped with nociceptors that allow for the sensation of touch, heat, cold, and pain, facilitating interaction with the environment. The skin's sensory roles are essential for an individual's movement, protection, andinteraction with the environment.

Diagnostic indicator:Skin characteristics such aspigmentation, smoothness, elasticity, and turgor provide insights into an individual's overall health status. Skin assessment is often a crucialpartof a person's physical examination.[10][11]

Cell division, desquamation, and sheddingin the skin:Cell division occurs in the stratum basale. Basal cells (young keratinocytes)begin the synthesis of keratinous tonofilaments, whichare grouped into bundles called tonofibrils. Older keratinocytes are then pushed into the stratum spinosum after mitosis.Skincellsbegin toproduce keratohyalin granules with intermediate-associated proteins, filaggrin, and trichohyalin in the upper part of the spinous layer. Thisprocess helps aggregate keratin filaments and convert granular cells into cornified cells, known as keratinization. Cells also produce lamellar bodies during this stage.

Keratinocytescontinue to move into the stratum granulosum afterward, where they become flattened and diamond-shaped. The cells accumulate keratohyalin granules mixed between tonofibrils.Keratinocytesthen continue to the stratum corneum, flattening and losing organelles and nuclei. The keratohyalin granules turn tonofibrils into a homogenous keratin matrix.Cornified cells reach the surface and are desquamated when desmosomes disintegrate. The proteinase activity of kallikrein-related serine peptidase is triggered by lowered pH near the surface. The processes ofskinshedding and desquamation vary slightly by body region.Hairless skincomprisesmore layers, withtheadditionof thestratum lucidum. Thus, keratinocytes in body regions with hairless skin go through more layers before reaching the surface.[12][13]

The epidermisis derived from ectodermal tissue. The dermis and hypodermisare derived from mesodermal tissue from somites. The mesoderm is also responsible for the formation of Langerhans cells. Neural crest cells, responsible for specialized sensory nerve endings and melanocyte formation, migrate into the epidermis during epidermal development.[14][15]

Blood vessels and lymphatic vessels are found in the skin's dermal layer.Blood supply to the skin comprises 2 plexusesonebetween the papillary and reticular dermal layers and another between the dermis and subcutaneous tissues.Blood supply to the epidermis is through the superficial arteriovenous plexus (subepidermal/papillary plexus). These vessels are important for temperature regulation. The body regulates temperature by increasing blood flowto the skin, transferring heatfrom the bodyto the environment.The autonomic nervous system controls the changes in blood flow.Sympathetic stimulation results in vasoconstriction, resulting in heat retention.Conversely, vasodilationleads to heat loss. Vasodilation is the body's response to increased body temperature,resulting from inhibiting the sympathetic centers in the posterior hypothalamus. In contrast, decreased body temperature causes vasoconstriction.[16][17]

Nerves of the skin include both somatic and autonomic nerves. The somatic sensory systemtransmitspain (nociception), temperature, light touch, discriminative touch, vibration, pressure, and proprioception sensations to the central nervous system. Specialized cutaneous receptors and end organs mediate perception, including Merkel disks and Pacinian, Meissner, and Ruffini corpuscles. Autonomic innervation controls vasculature tone, hair root pilomotor stimulation, and sweating. The free nerve endings extend into the epidermis and are responsible for sensing pain, heat, and cold. These sensory structures are most numerous in the stratum granulosum layer andaround most hair follicles. Merkel disks sense light touch andreaches the stratum basale layer. The other nerve endings are found in the deeper portions of the skin and include the Pacinian, Meissner, and Ruffini corpuscles. The Paciniancorpusclessense deep pressure. The Meissner corpuscles sense low-frequency stimulation at the level of the dermal papillae.TheRuffini corpuscles sense pressure.[18][19][20]

The arrector pili muscles are bundles of smooth muscle fibers attached to the connective tissue sheath of hair follicles. Contraction of these muscles pulls the hair follicle outward, erecting the hair. The arrector pili also compress the sebaceous glands, facilitating sebum secretion. Hair does not exit perpendicularly but at an angle. The erection of hair, known as piloerection, produces goosebumps, giving the skin a bumpy appearance when exposed to cold temperatures.[21]Studies show that piloerection contributes to thermoregulation and stem cell growth.[22]

Langer lines, also known as cleavage lines, are topological lines used to defineskin tension.Theselines correspond to the alignment of collagen and elastic fibers in the reticular dermis. Less scarring occurs ifsurgical incisions are made along these lines.[23]

The skin's clinical significance spans all medical disciplines. A few are discussed below.

Dermatomes

Dermatomes areskin segments divided based on afferent nerve distribution, numbered according to spinal vertebral levels. Spinal nerves comprise8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygealnerve. Diseasessuch as shingles caused by varicella-zoster infection manifest pain and rashes in dermatomal patterns. Dermatomes also aid inlocalizing spinal injuries.

Squamous Cell Carcinoma

Squamous cell carcinoma is amalignancy arising from mutated keratinocytes,typically due to UV damage in individuals with type I or II skin types. These individuals typically have light skin, blue or green eyes, and red or blonde hair and burn without tanning.The lesions oftenappearasscaly, flaky, thick red patches that may bleed.Somesquamous cell carcinoma tumors resemble warts.This type of skin cancer can metastasize. Squamous cell carcinoma often arises from actinic keratosespremalignant lesions with cutaneous hornsdeveloping fromchronicUV damage.[24]

Basal Cell Carcinoma

Basal cell carcinoma is a malignant neoplasm of the basal layers of the epidermis. Unlikesquamous cell carcinoma, itis much less likely to metastasize.This type of skin cancer is more common in sun-exposed areas, often appearing as pearly papules on the face, with telangiectasias and a great tendency to ulcerate.

Melanoma

Melanoma is a highly invasive malignant melanocyte tumor that is fatal but rarer than skinsquamous cell carcinoma and basal cell carcinoma. This neoplasm's high metastatic potential is significantly mediated bylesiondepth.Melanoma can be found anywhere on the body and is typically irregularly pigmented but can be amelanotic.[25]

Langerhans Cell Histiocytosis

Langerhans cell histiocytosis is a type of cancer in which Langerhans cells accumulate in the body andformgranulomas, often in the bones, causing bone pain.These granulomas can also appear in the skin, producing rashes, erythematous papules, or blisters (seeImage.Histology, Trichodysplasia Spinulosa). Notably, Langerhans cellhistiocytosis can affect the pituitary gland, leading to diabetes insipidus, infertility, or other endocrine disorders due to hormone deficiencies. Pancytopenia is apotentially fatal Langerhans cellhistiocytosis complication, manifesting with anemia, thrombocytopenia, and leukocytopenia, caused by overcrowding of Langerhans cells in the bone marrow.[26]

Merkel Cell Carcinoma

Merkel cell carcinoma is an uncommon cancer of the Merkel cells. This tumor is categorized as a neuroendocrine small cell carcinoma. Clinically,Merkelcell carcinoma often presents as a painless, solitary cutaneous or subcutaneous nodule, sometimes with a cystic appearance. The nodule can be red, pink, violet, blue, or skin-colored. Lesions may ulcerate or have satellite lesions.Merkel cell carcinoma is typically smaller than 20 mm at diagnosis but shows rapid tumor growth over a few months.[27]

Pemphigus Vulgaris

Pemphigus vulgaris is an autoimmune disease that targets the desmosomes, the intercellular proteins connecting keratinocytes. Desmosome degradation results in acantholysis and the formation ofeasily ruptured blisters within the epidermis. The disease is characterized by a positive Nikolsky sign, where the epidermis peels away upon rubbing.

Bullous Pemphigoid

Bullous pemphigoid is a blistering disease that affects older adults, causing tense subepidermal blisters.The conditionis causedby antibodies targeting hemidesmosomes, which connect the epidermis to the dermis at the basement membrane. This condition is not acantholytic and does not show a positive Nikolsky sign.[28]

ScaldedSkinSyndrome

Scalded skin syndromearises fromthe effects of the exfoliative toxin released byStaphylococcal aureus. The condition manifests as generalized skin exfoliationwith apositiveNikolsky sign, a severely burned (intensely red) appearance, and fever.[29][30]

Drug Reactions

Various drug reactions manifest in the skin, including erythema multiforme and the syndromes of drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson, and toxic epidermal necrolysis. These conditions are often associated with certain medications, including sulfa-containing drugs,nonsteroidal anti-inflammatory drugs, and antiepileptics.[31][32]

The epidermis contains much of our normal flora,with the microbiome varying by body region. The microorganisms inhabiting our skin surfaces are nonpathogenic and can be commensal or mutualistic. The bacteria that tend to predominate are Staphylococcusepidermidis andS aureus, Cutibacterium acnes, Corynebacterium, Streptococcus, Candida, and Clostridium perfringens. However, infections may occur when the protective skin barrier is altered or breached.[33]

Histology, Trichodysplasia Spinulosa. The left column shows hematoxylin and eosin staining of healthy skin (A1) and trichodysplasia spinulosa lesional skin (B1) at low power. At high power, healthy (A2) and trichodysplasia spinulosa (B2) epidermis and (more...)

Cross Section, Layers of the Skin. This is a cross-section view of the hair follicles, hair roots and shafts, sweat glands, pores, epidermis, dermis, and hypodermis. The papillary and reticular layers are also included. The eccrine sweat gland is located (more...)

Cells of the Epidermis. The image shows stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, stratum basale, and dermis. Contributed by C Rowe

Disclosure: Hani Yousef declares no relevant financial relationships with ineligible companies.

Disclosure: Mandy Alhajj declares no relevant financial relationships with ineligible companies.

Disclosure: Adegbenro Fakoya declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Sharma declares no relevant financial relationships with ineligible companies.

Original post:
Anatomy, Skin (Integument), Epidermis - StatPearls - NCBI Bookshelf

The weather is getting cooler and many of us are turning to hot showers and baths to warm up and wind down.

But what actually happens to your skin when you have really hot showers or baths?

Your skin is your largest organ, and has two distinct parts: the epidermis on the outside, and the dermis on the inside.

The epidermis is made up of billions of cells that lay in four layers in thin skin (such as on your eyelids) and five layers in thick skin (such as the on sole of your foot).

The cells (keratinocytes) in the deeper layers are held together by tight junctions. These cellular bridges make waterproof joins between neighbouring cells.

The cells on the outside of the epidermis have lost these cellular bridges and slough off at a rate of about 1,000 cells per one centimetre squared of skin per hour. For an average adult, thats 17 million cells per hour, every day.

Under the epidermis is the dermis, where we have blood vessels, nerves, hair follicles, pain receptors, pressure receptors and sweat glands.

Together, the epidermis and dermis (the skin):

So, your skin is important and worth looking after.

Washing daily can help prevent disease, and really hot baths often feel lovely and can help you relax. That said, there are some potential downsides.

Normally we have lots of healthy organisms called Staphyloccocus epidermis on the skin. These help increase the integrity of our skin layers (they make the bonds between cells stronger) and stimulate production of anti-microbial proteins.

These little critters like an acidic environment, such as the skins normal pH of between 4-6.

If the skin pH increases to around 7 (neutral), Staphyloccocus epidermis nasty cousin Staphyloccocus aureus also known as golden staph will try to take over and cause infections.

Having a hot shower or bath can increase your skins pH, which may ultimately benefit golden staph.

Being immersed in really hot water also pulls a lot of moisture from your dermis, and makes you lose water via sweat.

This makes your skin drier, and causes your kidneys to excrete more water, making more urine.

Staying in a hot bath for a long time can reduce your blood pressure, but increase your heart rate. People with low blood pressure or heart problems should speak to their doctor before having a long hot shower or bath.

Heat from the shower or bath can activate the release of cytokines (inflammatory molecules), histamines (which are involved in allergic reactions), and increase the number of sensory nerves. All of this can lead to itchiness after a very hot shower or bath.

Some people can get hives (itchy raised bumps that look red on lighter skin and brown or purple on darker skin) after hot showers or baths, which is a form of chronic inducible urticaria. Its fairly rare and is usually managed with antihistamines.

People with sensitive skin or chronic skin conditions such as urticaria, dermatitis, eczema, rosacea, psoriasis or acne should avoid really hot showers or baths. They dry out the skin and leave these people more prone to flare ups.

The skin on your hands or feet is least sensitive to hot and cold, so always use your wrist, not your hands, to test water temperature if youre bathing a child, older person, or a disabled person.

The skin on your buttocks is the most sensitive to hot and cold. This is why sometimes you think the bath is OK when you first step in, but once you sit down it burns your bum.

You might have heard women like hotter water temperature than men but thats not really supported by the research evidence. However, across your own body you have highly variable areas of thermal sensitivity, and everyone is highly variable, regardless of sex.

Moisturising after a hot bath or shower can help, but check if your moisturiser is up to the task.

To improve the skin barrier, your moisturiser needs to contain a mix of:

Not all moisturisers are actually good at reducing the moisture loss from your skin. You still might experience dryness and itchiness as your skin recovers if youve been having a lot of really hot showers and baths.

If youre itching after a hot shower or bath, try taking cooler, shorter showers and avoid reusing sponges, loofahs, or washcloths (which may harbour bacteria).

You can also try patting your skin dry, instead of rubbing it with a towel. Applying a hypoallergenic moisturising cream, like sorbolene, to damp skin can also help.

If your symptoms dont improve, see your doctor.

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The heart is a muscular organ found in humans and other animals. This organ pumps blood through the blood vessels.[1] The heart and blood vessels together make the circulatory system.[2] The pumped blood carries oxygen and nutrients to the tissue, while carrying metabolic waste such as carbon dioxide to the lungs. In humans, the heart is approximately the size of a closed fist and is located between the lungs, in the middle compartment of the chest, called the mediastinum.[4]

An illustration of the anterior view of the human heart

In humans, the heart is divided into four chambers: upper left and right atria and lower left and right ventricles.[5][6] Commonly, the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart. In a healthy heart, blood flows one way through the heart due to heart valves, which prevent backflow.[4] The heart is enclosed in a protective sac, the pericardium, which also contains a small amount of fluid. The wall of the heart is made up of three layers: epicardium, myocardium, and endocardium.[8]

The heart pumps blood with a rhythm determined by a group of pacemaker cells in the sinoatrial node. These generate an electric current that causes the heart to contract, traveling through the atrioventricular node and along the conduction system of the heart. In humans, deoxygenated blood enters the heart through the right atrium from the superior and inferior venae cavae and passes to the right ventricle. From here, it is pumped into pulmonary circulation to the lungs, where it receives oxygen and gives off carbon dioxide. Oxygenated blood then returns to the left atrium, passes through the left ventricle and is pumped out through the aorta into systemic circulation, traveling through arteries, arterioles, and capillarieswhere nutrients and other substances are exchanged between blood vessels and cells, losing oxygen and gaining carbon dioxidebefore being returned to the heart through venules and veins. The adult heart beats at a resting rate close to 72 beats per minute. Exercise temporarily increases the rate, but lowers it in the long term, and is good for heart health.

Cardiovascular diseases were the most common cause of death globally as of 2008, accounting for 30% of all human deaths.[12][13] Of these more than three-quarters are a result of coronary artery disease and stroke.[12] Risk factors include: smoking, being overweight, little exercise, high cholesterol, high blood pressure, and poorly controlled diabetes, among others.[14] Cardiovascular diseases do not frequently have symptoms but may cause chest pain or shortness of breath. Diagnosis of heart disease is often done by the taking of a medical history, listening to the heart-sounds with a stethoscope, as well as with ECG, and echocardiogram which uses ultrasound.[4] Specialists who focus on diseases of the heart are called cardiologists, although many specialties of medicine may be involved in treatment.[13]

Structure

Location and shape

The human heart is situated in the mediastinum, at the level of thoracic vertebrae T5T8. A double-membraned sac called the pericardium surrounds the heart and attaches to the mediastinum.[16] The back surface of the heart lies near the vertebral column, and the front surface, known as the sternocostal surface, sits behind the sternum and rib cartilages.[8] The upper part of the heart is the attachment point for several large blood vesselsthe venae cavae, aorta and pulmonary trunk. The upper part of the heart is located at the level of the third costal cartilage.[8] The lower tip of the heart, the apex, lies to the left of the sternum (8 to 9cm from the midsternal line) between the junction of the fourth and fifth ribs near their articulation with the costal cartilages.[8]

The largest part of the heart is usually slightly offset to the left side of the chest (levocardia). In a rare congenital disorder (dextrocardia) the heart is offset to the right side and is felt to be on the left because the left heart is stronger and larger, since it pumps to all body parts. Because the heart is between the lungs, the left lung is smaller than the right lung and has a cardiac notch in its border to accommodate the heart.[8]The heart is cone-shaped, with its base positioned upwards and tapering down to the apex.[8] An adult heart has a mass of 250350 grams (912oz).[17] The heart is often described as the size of a fist: 12cm (5in) in length, 8cm (3.5in) wide, and 6cm (2.5in) in thickness,[8] although this description is disputed, as the heart is likely to be slightly larger.[18] Well-trained athletes can have much larger hearts due to the effects of exercise on the heart muscle, similar to the response of skeletal muscle.[8]

Chambers

The heart has four chambers, two upper atria, the receiving chambers, and two lower ventricles, the discharging chambers. The atria open into the ventricles via the atrioventricular valves, present in the atrioventricular septum. This distinction is visible also on the surface of the heart as the coronary sulcus. There is an ear-shaped structure in the upper right atrium called the right atrial appendage, or auricle, and another in the upper left atrium, the left atrial appendage. The right atrium and the right ventricle together are sometimes referred to as the right heart. Similarly, the left atrium and the left ventricle together are sometimes referred to as the left heart. The ventricles are separated from each other by the interventricular septum, visible on the surface of the heart as the anterior longitudinal sulcus and the posterior interventricular sulcus.

The fibrous cardiac skeleton gives structure to the heart. It forms the atrioventricular septum, which separates the atria from the ventricles, and the fibrous rings, which serve as bases for the four heart valves.[21] The cardiac skeleton also provides an important boundary in the heart's electrical conduction system since collagen cannot conduct electricity. The interatrial septum separates the atria, and the interventricular septum separates the ventricles.[8] The interventricular septum is much thicker than the interatrial septum since the ventricles need to generate greater pressure when they contract.[8]

Valves

The heart, showing valves, arteries and veins. The white arrows show the normal direction of blood flow.

The heart has four valves, which separate its chambers. One valve lies between each atrium and ventricle, and one valve rests at the exit of each ventricle.[8]

The valves between the atria and ventricles are called the atrioventricular valves. Between the right atrium and the right ventricle is the tricuspid valve. The tricuspid valve has three cusps, which connect to chordae tendinae and three papillary muscles named the anterior, posterior, and septal muscles, after their relative positions. The mitral valve lies between the left atrium and left ventricle. It is also known as the bicuspid valve due to its having two cusps, an anterior and a posterior cusp. These cusps are also attached via chordae tendinae to two papillary muscles projecting from the ventricular wall.

The papillary muscles extend from the walls of the heart to valves by cartilaginous connections called chordae tendinae. These muscles prevent the valves from falling too far back when they close.[24] During the relaxation phase of the cardiac cycle, the papillary muscles are also relaxed and the tension on the chordae tendineae is slight. As the heart chambers contract, so do the papillary muscles. This creates tension on the chordae tendineae, helping to hold the cusps of the atrioventricular valves in place and preventing them from being blown back into the atria.[8][g]

Two additional semilunar valves sit at the exit of each of the ventricles. The pulmonary valve is located at the base of the pulmonary artery. This has three cusps which are not attached to any papillary muscles. When the ventricle relaxes blood flows back into the ventricle from the artery and this flow of blood fills the pocket-like valve, pressing against the cusps which close to seal the valve. The semilunar aortic valve is at the base of the aorta and also is not attached to papillary muscles. This too has three cusps which close with the pressure of the blood flowing back from the aorta.[8]

Right heart

The right heart consists of two chambers, the right atrium and the right ventricle, separated by a valve, the tricuspid valve.[8]

The right atrium receives blood almost continuously from the body's two major veins, the superior and inferior venae cavae. A small amount of blood from the coronary circulation also drains into the right atrium via the coronary sinus, which is immediately above and to the middle of the opening of the inferior vena cava.[8] In the wall of the right atrium is an oval-shaped depression known as the fossa ovalis, which is a remnant of an opening in the fetal heart known as the foramen ovale.[8] Most of the internal surface of the right atrium is smooth, the depression of the fossa ovalis is medial, and the anterior surface has prominent ridges of pectinate muscles, which are also present in the right atrial appendage.[8]

The right atrium is connected to the right ventricle by the tricuspid valve.[8] The walls of the right ventricle are lined with trabeculae carneae, ridges of cardiac muscle covered by endocardium. In addition to these muscular ridges, a band of cardiac muscle, also covered by endocardium, known as the moderator band reinforces the thin walls of the right ventricle and plays a crucial role in cardiac conduction. It arises from the lower part of the interventricular septum and crosses the interior space of the right ventricle to connect with the inferior papillary muscle.[8] The right ventricle tapers into the pulmonary trunk, into which it ejects blood when contracting. The pulmonary trunk branches into the left and right pulmonary arteries that carry the blood to each lung. The pulmonary valve lies between the right heart and the pulmonary trunk.[8]

Left heart

The left heart has two chambers: the left atrium and the left ventricle, separated by the mitral valve.[8]

The left atrium receives oxygenated blood back from the lungs via one of the four pulmonary veins. The left atrium has an outpouching called the left atrial appendage. Like the right atrium, the left atrium is lined by pectinate muscles.[25] The left atrium is connected to the left ventricle by the mitral valve.[8]

The left ventricle is much thicker as compared with the right, due to the greater force needed to pump blood to the entire body. Like the right ventricle, the left also has trabeculae carneae, but there is no moderator band. The left ventricle pumps blood to the body through the aortic valve and into the aorta. Two small openings above the aortic valve carry blood to the heart muscle; the left coronary artery is above the left cusp of the valve, and the right coronary artery is above the right cusp.[8]

Wall

The heart wall is made up of three layers: the inner endocardium, middle myocardium and outer epicardium. These are surrounded by a double-membraned sac called the pericardium.

The innermost layer of the heart is called the endocardium. It is made up of a lining of simple squamous epithelium and covers heart chambers and valves. It is continuous with the endothelium of the veins and arteries of the heart, and is joined to the myocardium with a thin layer of connective tissue.[8] The endocardium, by secreting endothelins, may also play a role in regulating the contraction of the myocardium.[8]

The middle layer of the heart wall is the myocardium, which is the cardiac musclea layer of involuntary striated muscle tissue surrounded by a framework of collagen. The cardiac muscle pattern is elegant and complex, as the muscle cells swirl and spiral around the chambers of the heart, with the outer muscles forming a figure 8 pattern around the atria and around the bases of the great vessels and the inner muscles, forming a figure 8 around the two ventricles and proceeding toward the apex. This complex swirling pattern allows the heart to pump blood more effectively.[8]

There are two types of cells in cardiac muscle: muscle cells which have the ability to contract easily, and pacemaker cells of the conducting system. The muscle cells make up the bulk (99%) of cells in the atria and ventricles. These contractile cells are connected by intercalated discs which allow a rapid response to impulses of action potential from the pacemaker cells. The intercalated discs allow the cells to act as a syncytium and enable the contractions that pump blood through the heart and into the major arteries.[8] The pacemaker cells make up 1% of cells and form the conduction system of the heart. They are generally much smaller than the contractile cells and have few myofibrils which gives them limited contractibility. Their function is similar in many respects to neurons.[8] Cardiac muscle tissue has autorhythmicity, the unique ability to initiate a cardiac action potential at a fixed ratespreading the impulse rapidly from cell to cell to trigger the contraction of the entire heart.[8]

There are specific proteins expressed in cardiac muscle cells.[26][27] These are mostly associated with muscle contraction, and bind with actin, myosin, tropomyosin, and troponin. They include MYH6, ACTC1, TNNI3, CDH2 and PKP2. Other proteins expressed are MYH7 and LDB3 that are also expressed in skeletal muscle.[28]

Pericardium

The pericardium is the sac that surrounds the heart. The tough outer surface of the pericardium is called the fibrous membrane. This is lined by a double inner membrane called the serous membrane that produces pericardial fluid to lubricate the surface of the heart. The part of the serous membrane attached to the fibrous membrane is called the parietal pericardium, while the part of the serous membrane attached to the heart is known as the visceral pericardium. The pericardium is present in order to lubricate its movement against other structures within the chest, to keep the heart's position stabilised within the chest, and to protect the heart from infection.[30]

Coronary circulation

Heart tissue, like all cells in the body, needs to be supplied with oxygen, nutrients and a way of removing metabolic wastes. This is achieved by the coronary circulation, which includes arteries, veins, and lymphatic vessels. Blood flow through the coronary vessels occurs in peaks and troughs relating to the heart muscle's relaxation or contraction.[8]

Heart tissue receives blood from two arteries which arise just above the aortic valve. These are the left main coronary artery and the right coronary artery. The left main coronary artery splits shortly after leaving the aorta into two vessels, the left anterior descending and the left circumflex artery. The left anterior descending artery supplies heart tissue and the front, outer side, and septum of the left ventricle. It does this by branching into smaller arteriesdiagonal and septal branches. The left circumflex supplies the back and underneath of the left ventricle. The right coronary artery supplies the right atrium, right ventricle, and lower posterior sections of the left ventricle. The right coronary artery also supplies blood to the atrioventricular node (in about 90% of people) and the sinoatrial node (in about 60% of people). The right coronary artery runs in a groove at the back of the heart and the left anterior descending artery runs in a groove at the front. There is significant variation between people in the anatomy of the arteries that supply the heart. The arteries divide at their furthest reaches into smaller branches that join at the edges of each arterial distribution.[8]

The coronary sinus is a large vein that drains into the right atrium, and receives most of the venous drainage of the heart. It receives blood from the great cardiac vein (receiving the left atrium and both ventricles), the posterior cardiac vein (draining the back of the left ventricle), the middle cardiac vein (draining the bottom of the left and right ventricles), and small cardiac veins. The anterior cardiac veins drain the front of the right ventricle and drain directly into the right atrium.[8]

Small lymphatic networks called plexuses exist beneath each of the three layers of the heart. These networks collect into a main left and a main right trunk, which travel up the groove between the ventricles that exists on the heart's surface, receiving smaller vessels as they travel up. These vessels then travel into the atrioventricular groove, and receive a third vessel which drains the section of the left ventricle sitting on the diaphragm. The left vessel joins with this third vessel, and travels along the pulmonary artery and left atrium, ending in the inferior tracheobronchial node. The right vessel travels along the right atrium and the part of the right ventricle sitting on the diaphragm. It usually then travels in front of the ascending aorta and then ends in a brachiocephalic node.

Nerve supply

The heart receives nerve signals from the vagus nerve and from nerves arising from the sympathetic trunk. These nerves act to influence, but not control, the heart rate. Sympathetic nerves also influence the force of heart contraction. Signals that travel along these nerves arise from two paired cardiovascular centres in the medulla oblongata. The vagus nerve of the parasympathetic nervous system acts to decrease the heart rate, and nerves from the sympathetic trunk act to increase the heart rate.[8] These nerves form a network of nerves that lies over the heart called the cardiac plexus.[8]

The vagus nerve is a long, wandering nerve that emerges from the brainstem and provides parasympathetic stimulation to a large number of organs in the thorax and abdomen, including the heart. The nerves from the sympathetic trunk emerge through the T1T4 thoracic ganglia and travel to both the sinoatrial and atrioventricular nodes, as well as to the atria and ventricles. The ventricles are more richly innervated by sympathetic fibers than parasympathetic fibers. Sympathetic stimulation causes the release of the neurotransmitter norepinephrine (also known as noradrenaline) at the neuromuscular junction of the cardiac nerves[citation needed]. This shortens the repolarisation period, thus speeding the rate of depolarisation and contraction, which results in an increased heart rate. It opens chemical or ligand-gated sodium and calcium ion channels, allowing an influx of positively charged ions.[8] Norepinephrine binds to the beta1 receptor.[8]

Development

The heart is the first functional organ to develop and starts to beat and pump blood at about three weeks into embryogenesis. This early start is crucial for subsequent embryonic and prenatal development.

The heart derives from splanchnopleuric mesenchyme in the neural plate which forms the cardiogenic region. Two endocardial tubes form here that fuse to form a primitive heart tube known as the tubular heart.[36] Between the third and fourth week, the heart tube lengthens, and begins to fold to form an S-shape within the pericardium. This places the chambers and major vessels into the correct alignment for the developed heart. Further development will include the formation of the septa and the valves and the remodeling of the heart chambers. By the end of the fifth week, the septa are complete, and by the ninth week, the heart valves are complete.[8]

Before the fifth week, there is an opening in the fetal heart known as the foramen ovale. The foramen ovale allowed blood in the fetal heart to pass directly from the right atrium to the left atrium, allowing some blood to bypass the lungs. Within seconds after birth, a flap of tissue known as the septum primum that previously acted as a valve closes the foramen ovale and establishes the typical cardiac circulation pattern. A depression in the surface of the right atrium remains where the foramen ovale was, called the fossa ovalis.[8]

The embryonic heart begins beating at around 22 days after conception (5 weeks after the last normal menstrual period, LMP). It starts to beat at a rate near to the mother's which is about 7580 beats per minute (bpm). The embryonic heart rate then accelerates and reaches a peak rate of 165185 bpm early in the early 7th week (early 9th week after the LMP).[37][38] After 9 weeks (start of the fetal stage) it starts to decelerate, slowing to around 145 (25) bpm at birth. There is no difference in female and male heart rates before birth.[39]

Physiology

Blood flow

The heart functions as a pump in the circulatory system to provide a continuous flow of blood throughout the body. This circulation consists of the systemic circulation to and from the body and the pulmonary circulation to and from the lungs. Blood in the pulmonary circulation exchanges carbon dioxide for oxygen in the lungs through the process of respiration. The systemic circulation then transports oxygen to the body and returns carbon dioxide and relatively deoxygenated blood to the heart for transfer to the lungs.[8]

The right heart collects deoxygenated blood from two large veins, the superior and inferior venae cavae. Blood collects in the right and left atrium continuously.[8] The superior vena cava drains blood from above the diaphragm and empties into the upper back part of the right atrium. The inferior vena cava drains the blood from below the diaphragm and empties into the back part of the atrium below the opening for the superior vena cava. Immediately above and to the middle of the opening of the inferior vena cava is the opening of the thin-walled coronary sinus.[8] Additionally, the coronary sinus returns deoxygenated blood from the myocardium to the right atrium. The blood collects in the right atrium. When the right atrium contracts, the blood is pumped through the tricuspid valve into the right ventricle. As the right ventricle contracts, the tricuspid valve closes and the blood is pumped into the pulmonary trunk through the pulmonary valve. The pulmonary trunk divides into pulmonary arteries and progressively smaller arteries throughout the lungs, until it reaches capillaries. As these pass by alveoli carbon dioxide is exchanged for oxygen. This happens through the passive process of diffusion.

In the left heart, oxygenated blood is returned to the left atrium via the pulmonary veins. It is then pumped into the left ventricle through the mitral valve and into the aorta through the aortic valve for systemic circulation. The aorta is a large artery that branches into many smaller arteries, arterioles, and ultimately capillaries. In the capillaries, oxygen and nutrients from blood are supplied to body cells for metabolism, and exchanged for carbon dioxide and waste products.[8] Capillary blood, now deoxygenated, travels into venules and veins that ultimately collect in the superior and inferior vena cavae, and into the right heart.

Cardiac cycle

The cardiac cycle is the sequence of events in which the heart contracts and relaxes with every heartbeat. The period of time during which the ventricles contract, forcing blood out into the aorta and main pulmonary artery, is known as systole, while the period during which the ventricles relax and refill with blood is known as diastole. The atria and ventricles work in concert, so in systole when the ventricles are contracting, the atria are relaxed and collecting blood. When the ventricles are relaxed in diastole, the atria contract to pump blood to the ventricles. This coordination ensures blood is pumped efficiently to the body.[8]

At the beginning of the cardiac cycle, the ventricles are relaxing. As they do so, they are filled by blood passing through the open mitral and tricuspid valves. After the ventricles have completed most of their filling, the atria contract, forcing further blood into the ventricles and priming the pump. Next, the ventricles start to contract. As the pressure rises within the cavities of the ventricles, the mitral and tricuspid valves are forced shut. As the pressure within the ventricles rises further, exceeding the pressure with the aorta and pulmonary arteries, the aortic and pulmonary valves open. Blood is ejected from the heart, causing the pressure within the ventricles to fall. Simultaneously, the atria refill as blood flows into the right atrium through the superior and inferior vena cavae, and into the left atrium through the pulmonary veins. Finally, when the pressure within the ventricles falls below the pressure within the aorta and pulmonary arteries, the aortic and pulmonary valves close. The ventricles start to relax, the mitral and tricuspid valves open, and the cycle begins again.

Cardiac output

Cardiac output (CO) is a measurement of the amount of blood pumped by each ventricle (stroke volume) in one minute. This is calculated by multiplying the stroke volume (SV) by the beats per minute of the heart rate (HR). So that: CO = SV x HR.[8]The cardiac output is normalized to body size through body surface area and is called the cardiac index.

The average cardiac output, using an average stroke volume of about 70mL, is 5.25 L/min, with a normal range of 4.08.0 L/min.[8] The stroke volume is normally measured using an echocardiogram and can be influenced by the size of the heart, physical and mental condition of the individual, sex, contractility, duration of contraction, preload and afterload.[8]

Preload refers to the filling pressure of the atria at the end of diastole, when the ventricles are at their fullest. A main factor is how long it takes the ventricles to fill: if the ventricles contract more frequently, then there is less time to fill and the preload will be less.[8] Preload can also be affected by a person's blood volume. The force of each contraction of the heart muscle is proportional to the preload, described as the Frank-Starling mechanism. This states that the force of contraction is directly proportional to the initial length of muscle fiber, meaning a ventricle will contract more forcefully, the more it is stretched.[8]

Afterload, or how much pressure the heart must generate to eject blood at systole, is influenced by vascular resistance. It can be influenced by narrowing of the heart valves (stenosis) or contraction or relaxation of the peripheral blood vessels.[8]

The strength of heart muscle contractions controls the stroke volume. This can be influenced positively or negatively by agents termed inotropes.[41] These agents can be a result of changes within the body, or be given as drugs as part of treatment for a medical disorder, or as a form of life support, particularly in intensive care units. Inotropes that increase the force of contraction are "positive" inotropes, and include sympathetic agents such as adrenaline, noradrenaline and dopamine.[42] "Negative" inotropes decrease the force of contraction and include calcium channel blockers.[41]

Electrical conduction

The normal rhythmical heart beat, called sinus rhythm, is established by the heart's own pacemaker, the sinoatrial node (also known as the sinus node or the SA node). Here an electrical signal is created that travels through the heart, causing the heart muscle to contract. The sinoatrial node is found in the upper part of the right atrium near to the junction with the superior vena cava.[43] The electrical signal generated by the sinoatrial node travels through the right atrium in a radial way that is not completely understood. It travels to the left atrium via Bachmann's bundle, such that the muscles of the left and right atria contract together.[44][45][46] The signal then travels to the atrioventricular node. This is found at the bottom of the right atrium in the atrioventricular septum, the boundary between the right atrium and the left ventricle. The septum is part of the cardiac skeleton, tissue within the heart that the electrical signal cannot pass through, which forces the signal to pass through the atrioventricular node only.[8] The signal then travels along the bundle of His to left and right bundle branches through to the ventricles of the heart. In the ventricles the signal is carried by specialized tissue called the Purkinje fibers which then transmit the electric charge to the heart muscle.[47]

Heart rate

Heart sounds of a 16 year old girl immediately after running, with a heart rate of 186 BPM.

The normal resting heart rate is called the sinus rhythm, created and sustained by the sinoatrial node, a group of pacemaking cells found in the wall of the right atrium. Cells in the sinoatrial node do this by creating an action potential. The cardiac action potential is created by the movement of specific electrolytes into and out of the pacemaker cells. The action potential then spreads to nearby cells.

When the sinoatrial cells are resting, they have a negative charge on their membranes. A rapid influx of sodium ions causes the membrane's charge to become positive; this is called depolarisation and occurs spontaneously.[8] Once the cell has a sufficiently high charge, the sodium channels close and calcium ions then begin to enter the cell, shortly after which potassium begins to leave it. All the ions travel through ion channels in the membrane of the sinoatrial cells. The potassium and calcium start to move out of and into the cell only once it has a sufficiently high charge, and so are called voltage-gated. Shortly after this, the calcium channels close and potassium channels open, allowing potassium to leave the cell. This causes the cell to have a negative resting charge and is called repolarisation. When the membrane potential reaches approximately 60 mV, the potassium channels close and the process may begin again.[8]

The ions move from areas where they are concentrated to where they are not. For this reason sodium moves into the cell from outside, and potassium moves from within the cell to outside the cell. Calcium also plays a critical role. Their influx through slow channels means that the sinoatrial cells have a prolonged "plateau" phase when they have a positive charge. A part of this is called the absolute refractory period. Calcium ions also combine with the regulatory protein troponin C in the troponin complex to enable contraction of the cardiac muscle, and separate from the protein to allow relaxation.[49]

The adult resting heart rate ranges from 60 to 100 bpm. The resting heart rate of a newborn can be 129 beats per minute (bpm) and this gradually decreases until maturity.[50] An athlete's heart rate can be lower than 60 bpm. During exercise the rate can be 150 bpm with maximum rates reaching from 200 to 220 bpm.[8]

Influences

The normal sinus rhythm of the heart, giving the resting heart rate, is influenced by a number of factors. The cardiovascular centres in the brainstem control the sympathetic and parasympathetic influences to the heart through the vagus nerve and sympathetic trunk.[51] These cardiovascular centres receive input from a series of receptors including baroreceptors, sensing the stretching of blood vessels and chemoreceptors, sensing the amount of oxygen and carbon dioxide in the blood and its pH. Through a series of reflexes these help regulate and sustain blood flow.[8]

Baroreceptors are stretch receptors located in the aortic sinus, carotid bodies, the venae cavae, and other locations, including pulmonary vessels and the right side of the heart itself. Baroreceptors fire at a rate determined by how much they are stretched, which is influenced by blood pressure, level of physical activity, and the relative distribution of blood. With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centers decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centers increase sympathetic stimulation and decrease parasympathetic stimulation.[8] There is a similar reflex, called the atrial reflex or Bainbridge reflex, associated with varying rates of blood flow to the atria. Increased venous return stretches the walls of the atria where specialized baroreceptors are located. However, as the atrial baroreceptors increase their rate of firing and as they stretch due to the increased blood pressure, the cardiac center responds by increasing sympathetic stimulation and inhibiting parasympathetic stimulation to increase heart rate. The opposite is also true.[8] Chemoreceptors present in the carotid body or adjacent to the aorta in an aortic body respond to the blood's oxygen, carbon dioxide levels. Low oxygen or high carbon dioxide will stimulate firing of the receptors.

Exercise and fitness levels, age, body temperature, basal metabolic rate, and even a person's emotional state can all affect the heart rate. High levels of the hormones epinephrine, norepinephrine, and thyroid hormones can increase the heart rate. The levels of electrolytes including calcium, potassium, and sodium can also influence the speed and regularity of the heart rate; low blood oxygen, low blood pressure and dehydration may increase it.[8]

Clinical significance

Diseases

Cardiovascular diseases, which include diseases of the heart, are the leading cause of death worldwide.[54] The majority of cardiovascular disease is noncommunicable and related to lifestyle and other factors, becoming more prevalent with ageing.[54] Heart disease is a major cause of death, accounting for an average of 30% of all deaths in 2008, globally.[12] This rate varies from a lower 28% to a high 40% in high-income countries.[13] Doctors that specialise in the heart are called cardiologists. Many other medical professionals are involved in treating diseases of the heart, including doctors, cardiothoracic surgeons, intensivists, and allied health practitioners including physiotherapists and dieticians.[55]

Ischemic heart disease

Coronary artery disease, also known as ischemic heart disease, is caused by atherosclerosisa build-up of fatty material along the inner walls of the arteries. These fatty deposits known as atherosclerotic plaques narrow the coronary arteries, and if severe may reduce blood flow to the heart.[56] If a narrowing (or stenosis) is relatively minor then the patient may not experience any symptoms. Severe narrowings may cause chest pain (angina) or breathlessness during exercise or even at rest. The thin covering of an atherosclerotic plaque can rupture, exposing the fatty centre to the circulating blood. In this case a clot or thrombus can form, blocking the artery, and restricting blood flow to an area of heart muscle causing a myocardial infarction (a heart attack) or unstable angina. In the worst case this may cause cardiac arrest, a sudden and utter loss of output from the heart. Obesity, high blood pressure, uncontrolled diabetes, smoking and high cholesterol can all increase the risk of developing atherosclerosis and coronary artery disease.[54][56]

Heart failure

Heart failure is defined as a condition in which the heart is unable to pump enough blood to meet the demands of the body.[59] Patients with heart failure may experience breathlessness especially when lying flat, as well as ankle swelling, known as peripheral oedema. Heart failure is the result of many diseases affecting the heart, but is most commonly associated with ischemic heart disease, valvular heart disease, or high blood pressure. Less common causes include various cardiomyopathies. Heart failure is frequently associated with weakness of the heart muscle in the ventricles (systolic heart failure), but can also be seen in patients with heart muscle that is strong but stiff (diastolic heart failure). The condition may affect the left ventricle (causing predominantly breathlessness), the right ventricle (causing predominantly swelling of the legs and an elevated jugular venous pressure), or both ventricles. Patients with heart failure are at higher risk of developing dangerous heart rhythm disturbances or arrhythmias.[59]

Cardiomyopathies

Cardiomyopathies are diseases affecting the muscle of the heart. Some cause abnormal thickening of the heart muscle (hypertrophic cardiomyopathy), some cause the heart to abnormally expand and weaken (dilated cardiomyopathy), some cause the heart muscle to become stiff and unable to fully relax between contractions (restrictive cardiomyopathy) and some make the heart prone to abnormal heart rhythms (arrhythmogenic cardiomyopathy). These conditions are often genetic and can be inherited, but some such as dilated cardiomyopathy may be caused by damage from toxins such as alcohol. Some cardiomyopathies such as hypertrophic cardiomopathy are linked to a higher risk of sudden cardiac death, particularly in athletes.[8] Many cardiomyopathies can lead to heart failure in the later stages of the disease.[59]

Valvular heart disease

Heart sounds of a 16 year old girl diagnosed with mitral valve prolapse and mitral regurgitation. Auscultating her heart, a systolic murmur and click is heard. Recorded with the stethoscope over the mitral valve.

Healthy heart valves allow blood to flow easily in one direction, and prevent it from flowing in the other direction. A diseased heart valve may have a narrow opening (stenosis), that restricts the flow of blood in the forward direction. A valve may otherwise be leaky, allowing blood to leak in the reverse direction (regurgitation). Valvular heart disease may cause breathlessness, blackouts, or chest pain, but may be asymptomatic and only detected on a routine examination by hearing abnormal heart sounds or a heart murmur. In the developed world, valvular heart disease is most commonly caused by degeneration secondary to old age, but may also be caused by infection of the heart valves (endocarditis). In some parts of the world rheumatic heart disease is a major cause of valvular heart disease, typically leading to mitral or aortic stenosis and caused by the body's immune system reacting to a streptococcal throat infection.[60]

Cardiac arrhythmias

While in the healthy heart, waves of electrical impulses originate in the sinus node before spreading to the rest of the atria, the atrioventricular node, and finally the ventricles (referred to as a normal sinus rhythm), this normal rhythm can be disrupted. Abnormal heart rhythms or arrhythmias may be asymptomatic or may cause palpitations, blackouts, or breathlessness. Some types of arrhythmia such as atrial fibrillation increase the long term risk of stroke.[62]

Some arrhythmias cause the heart to beat abnormally slowly, referred to as a bradycardia or bradyarrhythmia. This may be caused by an abnormally slow sinus node or damage within the cardiac conduction system (heart block).[63] In other arrhythmias the heart may beat abnormally rapidly, referred to as a tachycardia or tachyarrhythmia. These arrhythmias can take many forms and can originate from different structures within the heartsome arise from the atria (e.g. atrial flutter), some from the atrioventricular node (e.g. AV nodal re-entrant tachycardia) whilst others arise from the ventricles (e.g. ventricular tachycardia). Some tachyarrhythmias are caused by scarring within the heart (e.g. some forms of ventricular tachycardia), others by an irritable focus (e.g. focal atrial tachycardia), while others are caused by additional abnormal conduction tissue that has been present since birth (e.g. Wolff-Parkinson-White syndrome). The most dangerous form of heart racing is ventricular fibrillation, in which the ventricles quiver rather than contract, and which if untreated is rapidly fatal.[64]

Pericardial disease

The sac which surrounds the heart, called the pericardium, can become inflamed in a condition known as pericarditis. This condition typically causes chest pain that may spread to the back, and is often caused by a viral infection (glandular fever, cytomegalovirus, or coxsackievirus). Fluid can build up within the pericardial sac, referred to as a pericardial effusion. Pericardial effusions often occur secondary to pericarditis, kidney failure, or tumours, and frequently do not cause any symptoms. However, large effusions or effusions which accumulate rapidly can compress the heart in a condition known as cardiac tamponade, causing breathlessness and potentially fatal low blood pressure. Fluid can be removed from the pericardial space for diagnosis or to relieve tamponade using a syringe in a procedure called pericardiocentesis.

Congenital heart disease

Some people are born with hearts that are abnormal and these abnormalities are known as congenital heart defects. They may range from the relatively minor (e.g. patent foramen ovale, arguably a variant of normal) to serious life-threatening abnormalities (e.g. hypoplastic left heart syndrome). Common abnormalities include those that affect the heart muscle that separates the two side of the heart (a "hole in the heart", e.g. ventricular septal defect). Other defects include those affecting the heart valves (e.g. congenital aortic stenosis), or the main blood vessels that lead from the heart (e.g. coarctation of the aorta). More complex syndromes are seen that affect more than one part of the heart (e.g. Tetralogy of Fallot).

Some congenital heart defects allow blood that is low in oxygen that would normally be returned to the lungs to instead be pumped back to the rest of the body. These are known as cyanotic congenital heart defects and are often more serious. Major congenital heart defects are often picked up in childhood, shortly after birth, or even before a child is born (e.g. transposition of the great arteries), causing breathlessness and a lower rate of growth. More minor forms of congenital heart disease may remain undetected for many years and only reveal themselves in adult life (e.g., atrial septal defect).[66]

Channelopathies

Channelopathies can be categorized based on the organ system they affect. In the cardiovascular system, the electrical impulse required for each heart beat is provided by the electrochemical gradient of each heart cell. Because the beating of the heart depends on the proper movement of ions across the surface membrane, cardiac ion channelopathies form a major group of heart diseases.[68][69] Cardiac ion channelopathies may explain some of the cases of sudden death syndrome and sudden arrhythmic death syndrome.[70] Long QT syndrome is the most common form of cardiac channelopathy.

Diagnosis

Heart disease is diagnosed by the taking of a medical history, a cardiac examination, and further investigations, including blood tests, echocardiograms, electrocardiograms, and imaging. Other invasive procedures such as cardiac catheterisation can also play a role.

Examination

The cardiac examination includes inspection, feeling the chest with the hands (palpation) and listening with a stethoscope (auscultation).[77] It involves assessment of signs that may be visible on a person's hands (such as splinter haemorrhages), joints and other areas. A person's pulse is taken, usually at the radial artery near the wrist, in order to assess for the rhythm and strength of the pulse. The blood pressure is taken, using either a manual or automatic sphygmomanometer or using a more invasive measurement from within the artery. Any elevation of the jugular venous pulse is noted. A person's chest is felt for any transmitted vibrations from the heart, and then listened to with a stethoscope.

Heart sounds

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Heart - Wikipedia

EDMONTON, Alberta, June 02, 2025 (GLOBE NEWSWIRE) -- Quest PharmaTech Inc. (TSX-V: QPT) (“Quest” or the “Company”), a Canadian based pharmaceutical company developing products to improve the quality of life through investee companies and proprietary technologies, today provided a corporate update and announced that it has filed its annual audited financial statements for the year ended January 31, 2025, Management’s Discussion and Analysis and related filings on SEDAR+ (www.sedarplus.ca). The Company reported a net loss of $1.8 million, total liabilities of $1.2 million and total assets of $22.6 million, including the Company’s bonds of OQP Bio Inc. (“OQP Bio”) that were valued at $17 million as at January 31, 2025.

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Quest PharmaTech Provides Corporate Update

Tokyo, Japan and Cambridge, UK, 3 June 2025 – Nxera Pharma Co., Ltd. (“Nxera” or “the Company”; TSE 4565) today announces that its partner, Neurocrine Biosciences (“Neurocrine”) has dosed the first patient in its Phase 3 registrational program of NBI-1117568 (NBI-’568) as a potential treatment for schizophrenia, resulting in a payment of US$15 million to Nxera (Clinical Trial ID: NCT06963034). The US$15 million payment will be fully recognized as revenue in the second quarter of 2025.

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Nxera Pharma to Receive US$15 Million from Neurocrine Biosciences Following Dosing of First Patient in Phase 3 Trial of NBI-1117568

PRINCETON, N.J., May 23, 2025 (GLOBE NEWSWIRE) -- PMV Pharmaceuticals, Inc. (“PMV Pharma”; Nasdaq: PMVP), a precision oncology company pioneering the discovery and development of small molecule, tumor-agnostic therapies targeting p53, today announced that David H. Mack, Ph.D., President and Chief Executive Officer and Deepika Jalota, Pharm. D., Chief Development Officer, will participate at the following investor conferences. Management will also participate in one-on-one investor meetings.

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PMV Pharmaceuticals to Participate at Upcoming Investor Conferences

Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells[1] that give rise to other blood cells. This process is called haematopoiesis.[2] In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition.[3][4] In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

Haematopoiesis is the process by which all mature blood cells are produced. It must balance enormous production needs (the average person produces more than 500 billion blood cells every day) with the need to regulate the number of each blood cell type in the circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are multipotent and capable of extensive self-renewal.

Hematopoietic stem cells give rise to different types of blood cells, in lines called myeloid and lymphoid. Myeloid and lymphoid lineages both are involved in dendritic cell formation. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells.

The definition of hematopoietic stem cell has developed since they were first discovered in 1961.[5] The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent, oligopotent, and unipotent progenitors. Hematopoietic stem cells constitute 1:10,000 of cells in myeloid tissue.

HSC transplants are used in the treatment of cancers and other immune system disorders[6] due to their regenerative properties.[7]

They are round, non-adherent, with a rounded nucleus and low cytoplasm-to-nucleus ratio. In shape, hematopoietic stem cells resemble lymphocytes.

The very first hematopoietic stem cells during (mouse and human) embryonic development are found in aorta-gonad-mesonephros region and the vitelline and umbilical arteries.[8][9][10] Slightly later, HSCs are also found in the placenta, yolk sac, embryonic head, and fetal liver.[3][11]

Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe.[12] The cells can be removed as liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone).[citation needed]

A colony-forming unit is a subtype of HSC. (This sense of the term is different from colony-forming units of microbes, which is a cell counting unit.) There are various kinds of HSC colony-forming units:

The above CFUs are based on the lineage. Another CFU, the colony-forming unitspleen (CFU-S), was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in the spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or transit-amplifying cells rather than stem cells[citation needed].

Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope.[citation needed] Hematopoietic stem cells can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers (particularly CD34) are used to separate the rare hematopoietic stem cells from the surrounding blood cells. Hematopoietic stem cells lack expression of mature blood cell markers and are thus called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate hematopoietic stem cells. In addition, hematopoietic stem cells are characterised by their small size and low staining with vital dyes such as rhodamine 123 (rhodamine lo) or Hoechst 33342 (side population).

Hematopoietic stem cells are essential to haematopoiesis, the formation of the cells within blood. Hematopoietic stem cells can replenish all blood cell types (i.e., are multipotent) and self-renew. A small number of hematopoietic stem cells can expand to generate a very large number of daughter hematopoietic stem cells. This phenomenon is used in bone marrow transplantation,[13] when a small number of hematopoietic stem cells reconstitute the hematopoietic system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter hematopoietic stem cells must occur.

Stem cell self-renewal is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal.[2] There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically.

Hematopoietic stem cells, like all adult stem cells, mostly exist in a state of quiescence, or reversible growth arrest. The altered metabolism of quiescent HSCs helps the cells survive for extended periods of time in the hypoxic bone marrow environment.[14] When provoked by cell death or damage, Hematopoietic stem cells exit quiescence and begin actively dividing again. The transition from dormancy to propagation and back is regulated by the MEK/ERK pathway and PI3K/AKT/mTOR pathway.[15] Dysregulation of these transitions can lead to stem cell exhaustion, or the gradual loss of active Hematopoietic stem cells in the blood system.[15]

Hematopoietic stem cells have a higher potential than other immature blood cells to pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus, they may develop into T cells. In the case of fetuses and other extramedullary hematopoiesis. Hematopoietic stem cells may also settle in the liver or spleen and develop.

This enables Hematopoietic stem cells to be harvested directly from the blood.

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood.[16][17][13] It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).[16][17]

It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia.[17] In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.[17]

In order to harvest stem cells from the circulating peripheral blood, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), that induces cells to leave the bone marrow and circulate in the blood vessels.[18]In mammalian embryology, the first definitive Hematopoietic stem cells are detected in the AGM (aorta-gonad-mesonephros), and then massively expanded in the fetal liver prior to colonising the bone marrow before birth.[11]

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to autoimmune diseases[19][20] and hereditary skeletal dysplasias; notably malignant infantile osteopetrosis[21][22] and mucopolysaccharidosis.[23]

Stem cells can be used to regenerate different types of tissues. HCT is an established as therapy for chronic myeloid leukemia, acute lymphatic leukemia, aplastic anemia, and hemoglobinopathies, in addition to acute myeloid leukemia and primary immune deficiencies. Hematopoietic system regeneration is typically achieved within 24 weeks post-chemo- or irradiation therapy and HCT. HSCs are being clinically tested for their use in non-hematopoietic tissue regeneration.[24]

DNA strand breaks accumulate in long term hematopoietic stem cells during aging.[25] This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence.[25] Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template. The NHEJ pathway depends on several proteins including ligase 4, DNA polymerase mu and NHEJ factor 1 (NHEJ1, also known as Cernunnos or XLF).

DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes a progressive loss of hematopoietic stem cells during aging.[26] Deficiency of lig4 in pluripotent stem cells results in accumulation of DNA double-strand breaks and enhanced apoptosis.[27]

In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations with about a 40% decrease in bone marrow cell number that includes several hematopoietic lineages.[28] Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue.

Deficiency of NHEJ factor 1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time.[29] Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors.[30] These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation.[30]

The sensitivity of hematopoietic stem cells to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.[26] Rossi et al.[31] found that endogenous DNA damage accumulates with age even in wild type Hematopoietic stem cells, and suggested that DNA damage accrual may be an important physiological mechanism of stem cell aging.

A study shows the clonal diversity of hematopoietic stem cells gets drastically reduced around age 70 , substantiating a novel theory of ageing which could enable healthy aging.[32][33] Of note, the shift in clonal diversity during aging was previously reported in 2008[34] for the murine system by the Christa Muller-Sieburg laboratory in San Diego, California.

A cobblestone area-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated onto a confluent culture of stromal feeder layer,[35] a fraction of hematopoietic stem cells creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g. thymocytes into thymic nurse cells); on the other hand, when in vitro, lymphoid lineage cells creep beneath nurse-like cells, the process is called pseudoemperipolesis. This similar phenomenon is more commonly known in the HSC field by the cell culture terminology cobble stone area-forming cells (CAFC), which means areas or clusters of cells look dull cobblestone-like under phase contrast microscopy, compared to the other hematopoietic stem cells, which are refractile. This happens because the cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and, thus, not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1) and 41 integrins.[36]

Hematopoietic stem cells (HSC) cannot be easily observed directly, and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely the closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series is defined as the repopulation kinetic of the HSC.

The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes.[37] To prove this, several hundred experimental repopulation kinetics from clonal Thy-1lo SCA-1+ lin(B220, CD4, CD8, Gr-1, Mac-1 and Ter-119)[38] c-kit+ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria.

It was originally believed that all hematopoietic stem cells were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego, who illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1lo Sca-1+ lin c-kit+ HSC.[39][40][41] The results of these clonal studies led to the notion of lineage bias. Using the ratio = L / M {displaystyle rho =L/M} of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) hematopoietic stem cells repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3 10). Myeloid-biased (My-bi) hematopoietic stem cells give rise to very few lymphocytes resulting in ratios 0 < < 3, while lymphoid-biased (Ly-bi) hematopoietic stem cells generate very few myeloid cells, which results in lymphoid-to-myeloid ratios of > 10. All three types are normal types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin interleukin 7 (IL-7).[40]

Subsequently, other groups confirmed and highlighted the original findings.[42] For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties.[43] In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1+ lin c-kit+ HSC.[44] As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.

From Greek haimato-, combining form of haima 'blood', and from the Latinized form of Greek poietikos 'capable of making, creative, productive', from poiein 'to make, create'.[45]

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PALO ALTO, Calif., May 16, 2025 (GLOBE NEWSWIRE) -- Scilex Holding Company (Nasdaq: SCLX, “Scilex” or “Company”), an innovative revenue-generating company focused on acquiring, developing and commercializing non-opioid pain management products for the treatment of acute and chronic pain and neurodegenerative and cardiometabolic disease, today presented the presentation of post-hoc analysis of the C.L.E.A.R. trial (Corticosteroid Lumbar Epidural Analgesia in Radiculopathy) interpreting clinical meaningfulness of safety and efficacy of SP-102 (SEMDEXA™) for the treatment of lumbosacral radicular pain (LRP) at the 27th Annual Meeting of American Society of Interventional Pain Physicians (ASIPP), May 15-17, 2025 in Orlando, FL.

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SOMERVILLE, Mass., May 17, 2025 (GLOBE NEWSWIRE) -- Tessera Therapeutics, the biotechnology company pioneering a new approach in genetic medicine known as Gene Writing™, is presenting updates across its in vivo genetic medicine programs for AATD, PKU, and SCD, as well as advances in in vivo T cell therapies. These data were shared across four oral presentations and three poster presentations at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting taking place in New Orleans, Louisiana, May 13 – 17, 2025.

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WATERTOWN, Mass., May 17, 2025 (GLOBE NEWSWIRE) -- Tectonic Therapeutic, Inc. (NASDAQ: TECX) (“Tectonic”) today announced the complete results from Part A of the Phase 1b clinical trial of TX45 in patients with Group 2 Pulmonary Hypertension in Heart Failure with preserved Ejection Fraction (“PH-HFpEF”), which are being presented in a late-breaking, oral session at the European Society of Cardiology (ESC) Heart Failure 2025 Congress being held in Belgrade, Serbia. The results include the full cohort of 19 patients in Part A of the Phase 1b trial of TX45, Tectonic’s lead asset and a long-acting relaxin therapy. Interim data for 16 patients in the Phase 1b trial was previously reported in a press release on January 30, 2025.

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SHANGHAI, March 28, 2025 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (“Junshi Biosciences,” HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies, announced its financial results for the full year of 2024 and provided corporate updates.

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SAN DIEGO, March 28, 2025 (GLOBE NEWSWIRE) -- Turnstone Biologics Corp. (“Turnstone” or the “Company”) (Nasdaq: TSBX), a biotechnology company historically focused on the development of a differentiated approach to treat and cure patients with solid tumors by pioneering selected tumor-infiltrating lymphocyte (“Selected TIL”) therapy, today announced its financial results for the fourth quarter and full year ended December 31, 2024, and provided recent corporate updates.

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$171.4 million of cash, cash equivalents and marketable securities as of December 31, 2024

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– Lorundrostat 50 mg dose achieved a 15.4 mmHg absolute reduction and 7.9 mmHg placebo-adjusted reduction (p=0.001), assessed by 24hr ABPM at week 12, with favorable safety and tolerability profile –

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Bagsværd, Denmark, 29 March 2025 – Novo Nordisk today presented the full results from STRIDE, a phase 3b peripheral artery disease (PAD) outcomes trial investigating the effects of once-weekly injectable Ozempic® (semaglutide 1.0 mg) in adults with type 2 diabetes and PAD, at the American College of Cardiology's (ACC) Annual Scientific Session and Expo in Chicago, US1. These new data from the phase 3 trial were featured during a late-breaking clinical trial session at the ACC and simultaneously published today in The Lancet2.

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Ozempic® (once-weekly semaglutide 1.0 mg) shown to improve walking distance and quality of life in adults with type 2 diabetes and peripheral artery...

Bagsværd, Denmark, 29 March 2025 – Novo Nordisk today presented the full results from the SOUL cardiovascular outcomes trial, demonstrating that Rybelsus® (oral semaglutide) significantly reduced the risk of major adverse cardiovascular events in adults with type 2 diabetes and cardiovascular disease (CVD) and/or chronic kidney disease (CKD)1. These new data from the phase 3b trial were featured during a late-breaking clinical trial session at the American College of Cardiology's (ACC) Annual Scientific Session and Expo in Chicago, US and simultaneously published today in New England Journal of Medicine2.

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Novo Nordisk A/S: Rybelsus® (oral semaglutide 14 mg) demonstrates superior reduction in cardiovascular events in the SOUL trial at ACC 2025

Saint Herblain (France), March 31, 2025 – Valneva SE (Nasdaq: VALN; Euronext Paris: VLA), a specialty vaccine company, today announced that it has submitted a label extension application to the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK) to potentially expand the use of its chikungunya vaccine, IXCHIQ®, currently approved in adults1, to adolescents aged 12 to 17 years in the UK. This submission follows the recent positive opinion of the European Medicines Agency (EMA) on extension of IXCHIQ® label to adolescents in the European Union (EU)2.

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FORT LAUDERDALE, FLORIDA, March 21, 2025 (GLOBE NEWSWIRE) -- Bright Green Corporation (OTC: BGXX) (“Bright Green” or the “Company”) announced that on March 17, 2025, on behalf of the Company, Lynn Stockwell has asked the court to approve the “RSA” Restructuring Security Agreement, Disclosure Statement and Plan. The highlights of the Plan and Disclosure will provide new equity for the company to pay all creditors with approved claims in full, in addition the Company equity shareholders will retain their interests in the Company and are unimpaired with no dilution.

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Abstract

Induced pluripotent stem (iPS) cells are laboratory-produced cells that combine the biological advantages of somatic adult and stem cells for cell-based therapy. The reprogramming of cells, such as fibroblasts, to an embryonic stem cell-like state is done by the ectopic expression of transcription factors responsible for generating embryonic stem cell properties. These primary factors are octamer-binding transcription factor 4 (Oct3/4), sex-determining region Y-box 2 (Sox2), Krppel-like factor 4 (Klf4), and the proto-oncogene protein homolog of avian myelocytomatosis (c-Myc). The somatic cells can be easily obtained from the patient who will be subjected to cellular therapy and be reprogrammed to acquire the necessary high plasticity of embryonic stem cells. These cells have no ethical limitations involved, as in the case of embryonic stem cells, and display minimal immunological rejection risks after transplant. Currently, several clinical trials are in progress, most of them in phase I or II. Still, some inherent risks, such as chromosomal instability, insertional tumors, and teratoma formation, must be overcome to reach full clinical translation. However, with the clinical trials and extensive basic research studying the biology of these cells, a promising future for human cell-based therapies using iPS cells seems to be increasingly clear and close.

Keywords: induced pluripotent stem cells, regeneration, cellular therapy, stem cells, muscular dystrophy

Stem cells can be classified as totipotent, pluripotent, or multipotent cells according to their biological source and the capacity to differentiate into other cell types. Totipotent stem cells are found very early in embryonal development and can differentiate into all cell types in the organism, as well as into extraembryonic tissues. Pluripotent cells can be isolated from blastocysts or the umbilical cord immediately after birth, and are also able to differentiate into all tissue cells, except extraembryonic structures. However, certain disadvantages must be observed when considering these stem cells in regenerative medicine. These include the high risk of rejection and ethical issues when the isolation is performed from embryos. On the other hand, due to their high plasticity, pluripotent stem cells are considered ideal to obtaining the multiple cell types required after stem cell-based therapies.

Multipotent stem cells are isolated from adult tissues and have no ethical issues involved. These include hematopoietic, mesenchymal, and neural stem cells. Multipotent stem cells can be isolated from the patients subjected to treatment, with no risk of rejection, and be expanded in vitro for transplant. However, these cells display reduced plasticity, as they can only differentiate into specialized cell types present in specific tissues or organs, their main disadvantage. The ideal cellular population best suited for stem cell-based therapies should combine the high plasticity of embryonic stem cells and the convenient isolation from patients under treatment. To this end, induced pluripotent stem (iPS) cells were generated using embryonic or adult somatic cells. The somatic cells are subjected to the ectopic expression of transcription factors that induce the stem cell-like properties and the high plasticity required for cell therapy. Therefore, iPS cells can potentially revolutionize the field of regenerative medicine and provide new tools for stem cell research.

In the nineties, it was demonstrated that somatic cells could be reprogrammed to an undifferentiated state by transferring their nuclear content into unfertilized oocytes [1]. These results showed that cellular differentiation is reversible. Later, the resetting of a somatic epigenotype to a totipotent state was successfully achieved when adult thymocytes were fused with embryonic stem cells [2]. These and other pioneering studies [3] paved the way for the Nobel prize-awarded paper published by Takahashi and Yamanaka [4], who hypothesized that factors that play important roles in the maintenance of embryonic stem cell identity also play pivotal roles in the induction of pluripotency in somatic cells. In this study, mouse embryonic and adult fibroblasts were genetically reprogrammed to a pluripotent state, and the authors coined the term iPS cells. These cells were generated by using a retrovirus-based gene transfer system carrying the octamer-binding transcription factor 4 (Oct3/4), sex determining region Y-box 2 (Sox2), Krppel-like factor 4 (Klf4), and c-Myc transcription factors, all involved in pluripotency maintenance in embryonic stem cells [4].

IPS cell technology brings great promise to medicine, such as personalized cell therapy, disease modeling, and new drug development and screening. However, some challenges must be circumvented, such as reprogramming efficiency and the risks associated with chromosomal instability, insertional tumor development, and teratoma formation. In this context, here, we review the literature, present the main methods of cell reprogramming, and show some initial results of clinical tests. Besides, we discuss the possibility of applying iPS cells in the treatment of muscular dystrophies.

Various delivery methods have been used to insert reprogramming factors into somatic cells. These approaches can be divided into integrative, which involves the insertion of exogenous genetic material into the host genome, and non-integrative methods. The integrative systems include the use of viral vectors (lentivirus, retrovirus, and inducible or excisable retro or lentivirus) and non-viral vectors (linear or plasmid DNA fragments and transposons). Likewise, non-integrative systems include viral (Sendai virus and adenovirus) and non-viral vectors (episomal DNA vectors, RNAs, human artificial chromosomes (HAC), proteins, and small molecule compounds) [5,6] (Figure 1 and Table 1).

Somatic Cells Reprogramming Methods. The methods used to produce iPS cells can be classified into integrative viral, such as retrovirus (a), lentivirus (b), or inducible retro or lentivirus (c); and integrative non-viral, such as linear or circular DNA fragments (d) or transposons (e). In regards to non-integrative methods, they can also be separated as viral, such as adenovirus (f) or Sendai virus (g). Non-integrating non-viral methods are episomal DNA (h), RNAs (i), human artificial chromosome (HAC) (j), proteins (k), or small molecules (compounds) (l). The red DNA represents epigenetic inserted sequences for cellular reprogramming.

Comparison of multiple reprogramming techniques.

The expression of primarily just four transcription factors (c-Myc, Klf4, Oct4, and Sox2) is sufficient to reprogram somatic cells into a pluripotent state. The discovery of those factors related to the embryonic stem cell phenotype allowed the production of embryonic stem-like cells first from mouse embryonic and adult murine fibroblasts [4] and then from adult human dermal fibroblasts [7,8]. The Oct4 seems to be the most important reprogramming factor, whereas Klf4 and c-Myc can be replaced by Nanog and Lin28, for example [9].

The first experiments achieved the conversion of somatic cells into iPS cells using retroviral or lentiviral transduction of the transcription factors. However, these vectors become integrated into the cell genome and represent a risk of insertional mutagenesis [10]. Moreover, they may leave residual transgene sequences as part of the host genome, leading to unpredictable alterations in the phenotype of downstream applications. To reduce multiple proviral integrations of the transcription factors and to increase the efficiency of the retrovirus- or lentivirus-based reprogramming process, polycistronic RNA viral vectors were created. These constructs allowed the expression of all reprogramming factors driven by a single promoter, reducing the number of genomic insertions [11]. Once the integration of the reprogramming factors is achieved, it is also essential to control the extent of expression. To this end, the use of excisable Cre-loxP technology for site-specific recombination and inducible tetracycline- or doxycycline-based vector systems allowed greater control of inserted genes expression, reducing inefficient silencing and uncontrolled reactivation [5].

It is important to highlight that other factors have been described as being able to induce cellular pluripotency and self-renewal. Besides, several types of somatic cells have also been subjected to in vitro reprogramming, such as pancreatic cells, neural stem cells, stomach and liver cells, mature B lymphocytes, melanocytes, adipose stem cells, and keratinocytes. These results are summarized in the review published by Oldole and Fakoya [5].

The integrative non-viral technologies used to obtain iPS cells are based on the transference of DNA sequences using liposomes or electroporation [5], for example. It was possible to reprogram both mouse and human fibroblasts using a single multiprotein expression vector comprising the coding sequences of c-Myc, Klf4, Oct4, and Sox2 linked with 2A peptide [24]. When this single vector-based reprogramming system was combined with a piggyBac transposon, the authors successfully established reprogrammed human cell lines from embryonic fibroblasts with sustained pluripotency markers expression. PiggyBac is a mobile genetic element that includes a transposase enzyme that mediates gene transfer by targeted insertion and excision in the DNA. Moreover, Woltjen and collaborators showed the efficient reprogramming of murine and human embryonic fibroblasts using doxycycline-inducible transcription factors delivered by PiggyBac transposition. The authors also showed that the individual PiggyBac insertions could be removed from the iPS cell lines [15], being completely excised from its integration site in the original DNA sequence [25], which is a significant advantage.

The integrative methods for random or site-specific DNA insertion can affect normal cell function and physiology, including the transformation for tumorigenic cells, proliferation, and apoptosis control. Therefore, non-integrating viral vectors were constructed to generate iPS cells, the most promising of which is the Sendai virus, a negative-strand RNA virus [26]. The Sendai virus has the advantage of being an RNA virus that does not enter the nucleus and can produce large amounts of proteins [27]. Adenoviruses are also non-integrating viruses that appear to be excellent expression vehicles to generate iPS cells. They show DNA demethylation (a characteristic of reprogrammed cells), express endogenous pluripotency genes, and can generate multiple cells and tissues. However, the reprogramming efficiency of adenoviral vectors is only 0.001%0.0001% in mouse [28] and 0.0002% in human cells [29], several orders of magnitude lower, when compared to lentiviruses or retroviruses [5]. The use of viruses, even in non-integrating systems, requires refined steps to exclude reprogrammed cells with active replicating viruses. Moreover, viral vectors may elicit an innate and adaptive immune response against viral antigens after the transplant to patients. In this case, the transplanted cells would become the target of molecular and cellular cytotoxic pathways, directly compromising the engraftment and therapy success.

Non-integrating non-viral systems include the transient expression of reprogramming factors inserted as combined episomal minicircles or plasmids. These contain the complementary DNA (cDNA) of Oct3/4, Sox2, and Klf4 and another plasmid containing the c-Myc cDNA, for example. This technique resulted in iPS cells with no evidence of plasmid integration [16], suggesting that episomal plasmids may be the best option for clinical translation. This technique has already been used in the autologous induced stem cell-derived retinal treatment for macular degeneration [30]. Moreover, minicircle vectors are also used as a method for cellular reprogramming and consist of minimal vectors containing only the eukaryotic promoter and the cDNA(s) that will be expressed. This technique was able to reprogram human adipose stromal cells, but the reprogramming efficiency is substantially lower (~0.005%) when compared to lentiviral-based techniques, for example [31].

HACs are also non-integrative systems for gene delivery with the main advantage of being able to transfer multiple genes and large sequences, which can be combined with sequences that increase therapy security and expression control. The authors constructed two different HACs, and the reprogramming of mouse embryonic fibroblasts into iPS cells was better achieved when the artificial chromosome also encoded a p53-knockdown cassette. The iPS cells were uniformly generated, and a built-in safeguard system was included, consisting of a reintroduced HAC encoding the Herpes Simplex virus thymidine kinase, which allowed the targeted elimination of reprogrammed cells by ganciclovir treatment [19].

Another promising strategy focusing on non-integrative non-viral reprogramming methods for iPS cell generation is through RNA molecules, such as micro-RNAs. These sequences are small endogenous non-coding RNAs that play important post-transcriptional regulatory roles [32]. They also repress gene expression through translational inhibition or by promoting the degradation of mRNAs [33]. One study showed that normal human hair follicles could be reprogramed into human iPS cells via doxycycline-inducible pTet-On-tTS vectors inserted by electroporation. These constructs contained pre-microRNA members of the miR-302 cluster, including pre-miR-302a, 302b, 302c, and 302d [34]. Although the reprogramming efficiency was not reported in this study, it is known that iPS cells induced by micro-RNAs have a reprogramming efficiency above 10% and also have the lowest tumorigenicity rate. Although this approach has not yet been used in any clinical test, it may help in future developments in regenerative medicine [33]. More recently, micro-RNAs were used in combination with other reprogramming methods to increase reprogramming efficiency [5].

Another promising transgene-free approach is the direct mRNA transfection of synthetic modified coding sequences of the Yamanaka factors (c-Myc, Klf4, Oct4, and Sox2). This is a non-integrating method that can reprogram multiple human cell types to pluripotency very efficiently, avoiding the antiviral immune response. The authors further showed that the same technology efficiently directed the differentiation of RNA-induced pluripotent stem cells (RiPSCs) into terminally differentiated myogenic cells [35]. The method of the direct delivery of synthetically transcribed mRNAs triggered somatic cell reprogramming with higher efficiency when compared to retroviruses [35]. These mRNAs are commercially available, and the authors used cationic lipid delivery vehicles for transfection in cell culture for seven days [27]. Similar alternatives are emerging as the cellular introduction of all reprogramming factors via a single synthetic polycistronic RNA replicon that requires single transfection [36]. In this case, the transfection of adult fibroblasts resulted in an efficient generation of iPS cells with the expression of all stem cell markers tested, consistent global gene expression profile, and in vivo pluripotency for all three germ layers.

Transgene-free cellular reprogramming has also been achieved using recombinant proteins. In this case, the generation of stable iPS cells was possible by directly delivering the four reprogramming proteins fused with a cell-penetrating peptide [22]. However, it has been technically challenging to synthesize large amounts of bioactive proteins that can cross the plasma membrane. This problem associated with low efficiency shows that much remains to be done for the use of recombinant proteins as a viable method. Two research groups were able to make enough bioactive proteins in an E. coli expression system and to reprogram mouse [37] and human fibroblasts [22]. More recently, Weltner and collaborators also used Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 nuclease (CRISPR-Cas9)-based gene activation (CRISPRa) for reprogramming human skin fibroblasts into iPS cells [38]. CRISPR/Cas9 is a genome-editing tool powered by the design principle of the guide RNA that targets Cas9 to the desired DNA locus and by the high specificity and efficiency of CRISPR/Cas9-generated DNA breaks [39].

Another system for cellular reprogramming to generate iPS cells was the use of small-molecule compounds, which was developed by Hou and collaborators [23]. These authors used a combination of seven small molecules, but the efficiency achieved was only 0.2%. Small molecules have some advantages such as structural versatility, reasonable cost, easy handling, and no immune response. They can boost the application of iPS cells in disease therapy and drug screening. Some of these chemical compounds are valproic acid, trichostatin A (TSA), and 5-azacytidine, all capable of enhancing iPS cell generation [40]. One of the main advantages is that small (chemical) molecules can stimulate endogenous human cells to make tissue repair and regeneration in vivo, with no ectopic expression of factors. On the other hand, the method is time-consuming, and there is still a risk of genetic instability [6] to be overcome in future studies.

Despite all developments in the field of iPS cells, viral vector-based methods remain most popular among researchers [41]. Still, non-integrating non-viral self-excising vectors are more likely to be clinically applicable. To select an iPS cell reprogramming method, it is essential to maximize the capacity of cellular expansion in vitro, validate the detection and removal of incompletely differentiated cells, and search for genomic and epigenetic alterations. Probably, different somatic cell types will require different reprogramming methods to differentiate into the required terminal cell type in vivo.

Regardless of the reprogramming method, the risk of teratoma formation is inherent to iPS cells, as residual undifferentiated pluripotent cells retain very high plasticity. Although this risk has been reduced by highly sensitive methods for detecting remaining undifferentiated cells, teratoma formation cannot be ruled out [42]. Besides, c-Myc, one of the factors used for cellular reprogramming, is a well-known proto-oncogene, and its reactivation can give rise to transgene-driven tumor formation [43].

IPS cells can differentiate into cells from any of the three primary germ layers [44], with great potential for clinical applications. Neurodegenerative disorders, for example, and diseases in which in vitro differentiation and transplant protocols have been established using conventional embryonic stem cells, are areas of immediate interest for iPS-based cell therapy. IPS cell lines can be generated in virtually unlimited numbers from patients affected by diseases of known or unknown causes. These cells can differentiate in vitro into the disease-affected cell type and offer an opportunity to gain insight into the disease mechanism to identify novel disease-specific drugs. In Table 2, we show examples of iPS cells generated from patients with sporadic or genetic diseases.

Examples of terminally differentiated cells generated from induced pluripotent stem (iPS) cells.

Some drugs that are in clinical trials were derived from iPS cell studies. For example, cardiomyocyte-derived iPS cells obtained from patients with type-2 long QT syndrome were used to test the efficacy and potency of new and existing drugs [51]. In regenerative medicine, iPS cells can be used for tissue repair or replacement of injured tissues after cell transplantation. Early trials using iPS cell transplantation focused on age-related macular degeneration, and this is a refractory ocular disease that causes severe deterioration in the central vision due to senescence in the retinal pigment epithelium (RPE). Preclinical studies showed good results in various animal models and corroborated the first clinical trial that began in 2014 [54]. Kamao and collaborators generated human iPS cells derived from RPE (hiPSC-RPE) cells that met clinical use requirements, including cellular quality and quantity, reproducibility, and safety. After the transplant, autologous non-human primate iPSC-RPE cell sheets showed no immune rejection or tumor formation [55]. Then, in the clinical trial using iPS cells, the cells were generated from skin fibroblasts obtained from patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. In this test, autologous iPS cell-based therapy did not cause any significant adverse event [30]. However, the test with the second patient was discontinued due to genetic aberrations detected in the autologous iPS cells. With the rapid progress of genomic technologies, genetic aberrations in iPS cells will probably be reduced to a minimal level, with technological advances also focusing on automated closed culture systems [56].

Recent advances in genome editing technology have made it possible to repair genetic mutations in iPS cell lines derived from patients. Special attention has recently been focused on organoids derived from iPS cells, which are three-dimensional cellular structures mimicking part of the organization and functions of organs or tissues. Organoids were generated for various organs from both mouse and human stem cells, generating intestinal, renal, brain, and retinal structures, as well as liver organoid-like tissues, named liver buds [57]. Therefore, iPS cells-derived organoids can also be useful for drug testing and in vitro studies based on more complex cell models.

Moreover, iPS cells derived from cancer cells (cancer-iPS cells) can be a novel strategy for studying cancer. Primary cancer cells have been reprogrammed into iPS cells or at least to a pluripotent state, allowing the study and elucidation of some of the molecular mechanisms associated with cancer progression [58].

The possibility of using iPS cells in the treatment of various diseases has brought hope regarding their potential to treat an increasing number of conditions. As iPS cells can be differentiated into all different cell types, new prospects for studying diseases and developing treatments by regenerative medicine and drug screening have emerged. Therefore, a large number of clinical and preclinical trials are being carried out [59] to treat human diseases using iPS cells.

The reprogramming of somatic cells was demonstrated using different animal species, including mouse, rat [60], dog [61], a variety of non-human primate species [62], pig [63], horse [64], cow [65], goat [66], and sheep [67]. However, once the goal of pre-clinical trials is the clinical use of iPS cells, a number of these trials are being conducted using human iPS cells. For specific applications, however, human cells are expected to be rejected by the animal hosts, and immunosuppressive protocols are required for long-term observation. On the other hand, immunomodulating drugs may affect the disease phenotype, and careful planning of every step is necessary. Any stem-cell-based clinical trial must follow all precedents already established for the evaluation of small biological molecules or human tissue remodeling and must be safe and effective. The production of cells must be carried out in facilities that follow the current Good Manufacturing Practices (GMP) and have stringent quality control for reagents with well-defined product release and potency assays. GMP is a set of conditions that define the principles and details of the manufacturing process, quality control, evaluations, and documentation for a particular product. Moreover, the best delivery system of iPS cells must be evaluated for each disease, which can be the use of intravascular catheters or surgical injection, for example.

Human-derived iPS cell lines successfully repopulated the murine cirrhotic liver tissue with hepatic cells at various differentiation stages. They also secreted human-specific liver proteins into mouse blood at concentrations comparable to those of proteins secreted by human primary hepatocytes [68]. In other preclinical studies, iPS cells were generated using adult dsRed mouse dermal fibroblasts via retroviral induction, following transplantation into the eye of immune-compromised retinal degenerative mice. After thirty-three days of differentiation, a large proportion of the cells expressed the retinal progenitor cell marker Pax6 and photoreceptor markers. Therefore, adult fibroblast-derived iPS cells are a viable source for the production of retinal precursors to be used for transplantation and treatment of retinal degenerative disease [69]. IPS cells were also generated from nonobese diabetic mouse embryonic fibroblasts or nonobese diabetic mouse pancreas-derived epithelial cells and differentiated into functional pancreatic beta cells. The differentiated cells expressed diverse pancreatic beta-cell markers and released insulin in response to glucose and KCl stimulation. Moreover, the engrafted cells responded to glucose levels by secreting insulin, thereby normalizing blood glucose levels, showing that these cells may be an important tool to help in the treatment of diabetic patients [70]. Human cardiomyocytes derived from iPS cells are another source of cells capable of inducing myocardial regeneration for the recovery of cardiac function. These cells were established using human dermal fibroblasts transfected with a retrovirus carrying the conventional factors Oct3/4, Sox2, Klf4, and c-Myc. When the iPS cells were transplanted into the myocardial infarcted area in a porcine model of ischemic cardiomyopathy, the activation of WNT signaling pathways induced cardiomyogenic differentiation. It was also observed that the transplanted cells significantly improved cardiac function and attenuated left ventricular remodeling [71]. In another study, dopaminergic neurons derived from protein-induced human iPS cells exhibited gene expression, physiology, and electrophysiological properties similar to the dopaminergic neurons found in the midbrain. The transplantation of these cells significantly rescued the motor deficits of rats with striatal lesions, an experimental model of Parkinsons disease [72]. Moreover, after stroke-induced brain damage, adult human fibroblast-derived iPS cells were transplanted into the cortical lesion and, one week after the transplantation, there was the initial recovery of the forepaw movements. Moreover, engrafted cells exhibited electrophysiological properties of mature neurons and received synaptic input from host neurons [73].

In October 2018, 2.4 million iPS cells reprogrammed into dopaminergic precursor cell neurons were implanted into the brain of a patient in his 50s. In the three-hour procedure, the team deposited the cells into twelve sites, known to be centers of dopamine activity. The patient showed no significant adverse effects [74]. The first allogeneic clinical trial using iPS cells derived from mesenchymal stem cells for the treatment of graft-versus-host disease has also been reported, and no treatment-related serious adverse effects were observed [75]. Other clinical studies using iPS cells are being conducted in patients with heart failure [76,77]. Moreover, other tests have been approved for neural precursor cells for spinal cord injuries [78] and corneal epithelial cell sheets for corneal epithelial stem cell deficiency [79]. Thus, ongoing clinical tests provide a better understanding of clinical aspects involving immunosuppressants and fundamental elements such as genomic data that will pave the way for therapies using iPS cells.

The iPS cells have the potential to revolutionize the field of neurodegenerative diseases, which are characterized by the progressive deterioration of neuronal function. Therefore, multiple capacities are affected, leading to cognitive impairment, memory deficits, deficiency in motor function, loss of sensitivity, dysfunction of the autonomous brain system, changes in perception, and mood [80]. Among neurodegenerative diseases, Alzheimers disease is the most prevalent form of dementia, characterized by the accumulation of amyloid-beta (A) plaques and Tau-laden neurofibrillary tangles. Tau is a microtubule-associated protein found in the axons of the nerve cells, and these aggregates and tangles are the histopathological hallmarks of the disease [81]. The dysfunction and degeneration of neurons indeed underlie much of the observed decline in cognitive function, but various other types of non-neuronal cells are increasingly being implicated in the disease progression [82]. Therefore, iPS cells are emerging as an invaluable tool to better modeling the complex interactions that occur between multiple cell types in vivo. 3D and co-culture systems of iPS-derived cells in vitro hold promise to better understand the relevance of multiple cell types and the pathomechanisms that underlie the disease progression. Therefore, iPS cells have been generated from patients and healthy donors to study multiple genetic mutations in neurons, astrocytes, oligodendrocytes, microglia, pericytes, and vascular endothelial cells [83]. Moreover, a mutant Tau model derived from iPS cells was generated and showed several phenotypes associated with this neurodegenerative disease, including the pathogenic accumulation of Tau for drug screening [84]. Choi et al., 2014 showed a 3D culture model based on iPS cells that histopathologically reproduces the hallmarks of Alzheimers disease, including a robust extracellular deposition of A. This model was sensitive to drugs, which reversed the pathological phenotype [85]. The use of neural models derived from iPS cells can validate molecular mechanisms identified in the disease models in rodents, for example, and play an important role in the discovery and screening of new drugs [86].

Parkinsons disease is another important disease; being the second most common neurodegenerative disorder, it affects 2% to 3% of the population over 65 years of age. Characteristic features of Parkinsons disease include neuronal loss in specific areas of the substantia nigra and widespread intracellular protein (-synuclein) accumulation [87]. Due to the loss of dopaminergic neurons in localized regions of the brain, the use of human cells for therapeutic purposes has been studied with special attention. These assessments include iPS cells, whose good results supported the deployment of some studies that are already in the clinical phase. Pre-clinical studies have shown the efficient generation of iPS cells-derived dopaminergic motor neurons from non-human primates. Then, these cells were efficiently transplanted into a model of Parkinsons disease in rats [88]. Several new protocols have improved the efficiency of obtaining dopaminergic neurons from iPS cells for the study and modeling of Parkinsons disease [89]. The iPS cells used in some studies were mainly from patients carrying mutations in synuclein alpha, leucine-rich repeat kinase 2, PTEN-induced putative kinase 1, parkin RBR E3 ubiquitin-protein ligase, cytoplasmic protein sorting 35, and variants in glucosidase beta acid [90]. Although improvements are still needed, iPS cells make it possible to develop patient-specific disease models using disease-relevant cell types. Interestingly, using a human iPS cells-derived model of Parkinsons disease, it was found that the myocyte enhancer factor 2C-peroxisome proliferator-activated receptor- coactivator-1 (MEF2C-PGC1) pathway may be a new therapeutic target for Parkinsons disease. The data from this study provided mechanistic insight into geneenvironmental interaction in the pathogenesis of the disease [91]. Thus, it is important to develop models of neurodegenerative diseases using iPS cells because they involve a complex interplay of genetic alterations, transcriptional feedback, and endogenous control by transcription factors. Probably, the combination of different experimental approaches, using cellular systems and animal models, will increase the successful translation to the clinical practice [92].

In a successful pre-clinical study, the authors demonstrated that human dopaminergic neurons generated from iPS cells, and transplanted into a primate model of Parkinsons disease, established connections with the host monkey brain cells with no tumor formation after two years [93]. Immediately after the successful animal experiments, the Japanese research group implanted reprogrammed stem cells into the brain of a patient with Parkinsons disease for the first time in 2018 (as NEWS Reported by Nature https://www.nature.com/articles/d41586-018-07407-9).

Recently, extracellular vesicles/exosomes derived from iPS cells of different lineages were involved in neurological diseases. Extracellular vesicles are lipid-enclosed structures with a diameter of 301000 nm, carrying transmembrane and cytosolic proteins. Exosomes are a subset of extracellular vesicles, with a diameter ranging between 30 and 200 nm. Functionally, they play an important role in intercellular communications, immune modulation, senescence, proliferation, and differentiation in various biological processes, and are vital in maintaining tissue homeostasis [94]. On the other hand, and as cited before, abnormal protein aggregation has been implicated in many neurodegenerative processes that lead to human neurological disorders. Recent reports suggested that exosomes combine these two important characteristics, as they are involved in the intercellular transfer of macromolecules, such as proteins and RNAs, and seem to play an important role in the aggregate transmission among neurons [95]. The authors showed that extracellular vesicles from iPS cells carry proteins and mRNA that can induce or maintain pluripotency, which can be used in regenerative strategies for neural tissue [96]. If this is true, extracellular vesicles/exosomes derived from corrected iPS cells, which do not accumulate protein aggregates, may be safer for human treatment than iPS cells themselves [94]. The infusion of neuronal exosomes into the brains of a murine model of Alzheimers disease decreased the A peptide and amyloid depositions [97]. Moreover, exosomes obtained from stem cells were able to rescue dopaminergic neurons from apoptosis [98]. The authors showed that extracellular vesicles from mesenchymal stem cells, when injected into a mouse model of Alzheimers disease, reduced the A plaque burden and the number of dystrophic neurites in the cortex and hippocampus [99]. Extracellular vesicles were also derived from human iPS neural stem cells and used for stroke treatment [100]. The results using extracellular vesicles/exosomes obtained from iPS cells point to a promising future in the treatment of neurodegenerative diseases.

Muscular dystrophies (MD) are a group of genetic diseases that lead to skeletal muscle wasting and may affect many organs (multisystem) [101]. The terminal pathology often shows muscle fibers necrosis and muscle tissue replacement by fibrotic or adipose tissues. Currently, there is no cure for MD, and the available treatments are palliative or of limited effectiveness [102]. The most frequent and one of the most severe forms of all MD is the Duchenne muscular dystrophy (DMD), a muscle pathology caused by the lack of the protein dystrophin. In this case, previous cell-based therapies did not show satisfactory results after myoblast transplantation [103]. Myoblasts are the progeny of muscle satellite cells (SC), the main stem cell population found in adult skeletal muscles. Quiescent SCs are triggered to reenter into the cell cycle mainly by muscle damage, and the SC-derived myoblasts proliferate and fuse to form new multinucleated myofibers [101]. In most myoblast-based therapies, allogeneic cells were obtained from muscle biopsies from healthy donors, resulting in transplanted cell rejection by the immune system, with low surviving rates, poor dispersion, and differentiation [103,104,105]. With the advances of iPS cell technology, some of these issues are being addressed (Figure 2).

iPS cells in Duchene muscular dystrophy cell therapy. The somatic cells derived from specific patients with Duchenne muscular dystrophy (DMD) can be reprogrammed into iPS cells with reprogramming factors. These cells are then genetically corrected to express the protein dystrophin for the autologous muscular injection of muscle-committed cells.

One of the main problems in the application of stem cell therapy in muscle diseases is to obtain large numbers of cells for sufficient engraftment, and the use of iPS cells may overcome this obstacle. For this purpose, Darabi and colleagues [106] applied the conditional expression of Pax7 to iPS cells, a transcription factor that plays a role in SC proliferation. Then, Pax7+ iPS cells were obtained on a larger scale for transplant into a mouse dystrophic muscle, which showed dystrophin+ fibers with superior strength [106]. Moreover, the authors genetically restored the dystrophin expression in autologous iPS cells derived from DMD patients. For this, three corrective methods were used, which were exon knock-in, exon skipping, and frameshifting, and the exon knock-in was the most effective approach [107]. The Cas9 protein (CRISPR-associated protein 9), derived from type II CRISPR (clustered regularly interspaced short palindromic repeats) bacterial immune systems, is a technology that has also emerged as an approach capable of targeting the mutated dystrophin gene, aiming to rescue its expression in vitro in iPS cells derived from selected patients [108].

Moreover, using CRISPR-Cas9 technology with single guide RNA, dystrophin expression was restored by exon skipping through myoediting in iPS cells. The genetic alterations observed in the multiple patients included large deletions, point mutations, or duplications within the DMD gene. The corrected iPS cells efficiently restored the expression of dystrophin and the corresponding mechanical contraction force in derived cardiomyocytes [109]. In summary, several methods of gene editing have been applied for the correction of the DMD gene to allow the transplantation of genetically corrected autologous iPS cells. Of these, the CRISPR-Cas9 system, in particular, has passed multiple proof-of-principle tests and is now being used in pre-clinical trials (Figure 2).

Reprogrammed fibroblast- and myoblast-derived iPS cells were also obtained from patients with limb-girdle muscular dystrophy type 2D (LGMD2D). This disease is a sarcoglycanopathy caused by mutations in the SCGA gene, which provides instructions for making the alpha component of the sarcoglycan protein complex. This multiprotein complex plays a role in the anchoring of the dystrophin-glycoprotein complex (DGC) to the extracellular matrix and helps to maintain muscle fiber membrane integrity. The iPS cells were expanded and genetically corrected in vitro with a lentiviral vector carrying the human gene encoding the -sarcoglycan. Finally, the transplantation of mouse iPS cells into -sarcoglycan-null immunodeficient mice, an experimental model of the disease, resulted in the amelioration of the dystrophic phenotype [110]. This transplant also showed that iPS cells restored the compartment of SC, an essential checkpoint for sustained muscle regeneration.

Recently, Perepelina and collaborators generated iPS cells from EmeryDreifuss muscle dystrophy associated with the genetic variant LMNAp.Arg527Pro. Patient-specific peripheral blood mononuclear cells were reprogrammed using the Sendai virus system, and the authors comment that this is a useful tool to study laminopathies in vitro [111]. Moreover, using three-dimensional (3D) tissue engineering techniques, artificial skeletal muscle tissue was generated using iPS cells from patients with Duchenne, limb-girdle, or congenital muscular dystrophies [112]. In this way, artificial muscles recapitulated characteristics of human skeletal muscle tissue, providing an invaluable tool to study pathological mechanisms, drug testing, cell therapy, and the development of tissue replacement protocols.

The use of iPS cells still has many challenges ahead before they can be clinically used in the supportive treatment of patients with MD. Among these, we can cite the injection of iPS cells (or muscle-committed iPS-derived cells) into large muscles, the immunological recognition of proteins expressed only after the genetic correction, the capacity of cellular dispersion through the muscle, the number of therapeutic interventions needed to replenish cellular muscle populations, the ability to produce corrected SC for sustained muscle recovery, and the control of transplanted cells death.

To address these and other limitations, we propose that autologous iPS cells be submitted to multiple treatments aiming to improve cellular engraftment and clinical use. Besides the genetic correction of underlying pathological mutations, these cells can be further treated in culture to boost cell proliferation, long-term survival, dispersion in the muscle, differentiation into muscle fibers, and others. We proposed before the use of multiple combined in vitro treatments for adoptively transferred myoblasts for cell-based therapy, and these are summarized in [101]. These treatments include vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF), Wnt7a, Ursolic acid, and extracellular matrix components. Moreover, the recipient muscle to be injected with the corrected and boosted iPS cells can also be treated to favor the engraftment. These treatments include actinin receptor type 2B inhibitor, IL-6, JAK/STAT 3 inhibitor, growth factors, the coinjection of other supportive cell types, such as macrophages and fibroblasts, and others.

We believe that the correct choice for the ideal combination of the cell type to be reprogrammed into iPS cells, the technical procedure for genetic correction, the in vitro treatments to boost iPS cells, and the in vivo preparation of recipients muscles, hold the key for a more successful application of iPS cells in clinical translation. However, we believe that systemic treatments consisting of the injection of cells will not lead to individual muscle damage and strength improvement. The transplanted cells do not express the required repertoire of molecules necessary for endothelial transmigration. Probably, selected individual and more affected muscles are more likely to benefit from cellular-based therapies, followed by treatments that can increase injected cell dispersion within the muscle.

Currently, publicprivate partnership consortia are providing resources to form iPS cell banks for clinical and research purposes. These banks have coordinated standards to meet international criteria for quality-controlled repositories of iPS cells. Although the use of iPS cells for autologous therapy seems more appropriate, having allogeneic banks of iPS cells already generated and tested would reduce the time needed to start treatment, decrease costs, and increase the chances of recovery of treated individuals [113]. Thus, although many technical challenges must still be overcome, the technology of iPS cells has already taken a marked leap in clinical management and in vitro models to study and treat diseases.

D.G.B.: manuscript preparation and review; S.I.H.: manuscript review and preparation of figure; C.M.C.: manuscript preparation; L.A.A.: manuscript review and figure preparation; A.H.-P.: manuscript and figure preparation and review. All authors have read and agreed to the published version of the manuscript.

This work was funded by CNPq (Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico) grant numbers 407711/2012-0 and 421803/2017-7 and Fundao Oswaldo Cruz.

The authors declare no conflict of interest.

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