heart, organ that serves as a pump to circulate the blood. It may be a straight tube, as in spiders and annelid worms, or a somewhat more elaborate structure with one or more receiving chambers (atria) and a main pumping chamber (ventricle), as in mollusks. In fishes the heart is a folded tube, with three or four enlarged areas that correspond to the chambers in the mammalian heart. In animals with lungsamphibians, reptiles, birds, and mammalsthe heart shows various stages of evolution from a single to a double pump that circulates blood (1) to the lungs and (2) to the body as a whole.

In humans and other mammals and in birds, the heart is a four-chambered double pump that is the centre of the circulatory system. In humans it is situated between the two lungs and slightly to the left of centre, behind the breastbone; it rests on the diaphragm, the muscular partition between the chest and the abdominal cavity.

The heart consists of several layers of a tough muscular wall, the myocardium. A thin layer of tissue, the pericardium, covers the outside, and another layer, the endocardium, lines the inside. The heart cavity is divided down the middle into a right and a left heart, which in turn are subdivided into two chambers. The upper chamber is called an atrium (or auricle), and the lower chamber is called a ventricle. The two atria act as receiving chambers for blood entering the heart; the more muscular ventricles pump the blood out of the heart.

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The heart, although a single organ, can be considered as two pumps that propel blood through two different circuits. The right atrium receives venous blood from the head, chest, and arms via the large vein called the superior vena cava and receives blood from the abdomen, pelvic region, and legs via the inferior vena cava. Blood then passes through the tricuspid valve to the right ventricle, which propels it through the pulmonary artery to the lungs. In the lungs venous blood comes in contact with inhaled air, picks up oxygen, and loses carbon dioxide. Oxygenated blood is returned to the left atrium through the pulmonary veins. Valves in the heart allow blood to flow in one direction only and help maintain the pressure required to pump the blood.

The low-pressure circuit from the heart (right atrium and right ventricle), through the lungs, and back to the heart (left atrium) constitutes the pulmonary circulation. Passage of blood through the left atrium, bicuspid valve, left ventricle, aorta, tissues of the body, and back to the right atrium constitutes the systemic circulation. Blood pressure is greatest in the left ventricle and in the aorta and its arterial branches. Pressure is reduced in the capillaries (vessels of minute diameter) and is reduced further in the veins returning blood to the right atrium.

The pumping of the heart, or the heartbeat, is caused by alternating contractions and relaxations of the myocardium. These contractions are stimulated by electrical impulses from a natural pacemaker, the sinoatrial, or S-A, node located in the muscle of the right atrium. An impulse from the S-A node causes the two atria to contract, forcing blood into the ventricles. Contraction of the ventricles is controlled by impulses from the atrioventricular, or A-V, node located at the junction of the two atria. Following contraction, the ventricles relax, and pressure within them falls. Blood again flows into the atria, and an impulse from the S-A starts the cycle over again. This process is called the cardiac cycle. The period of relaxation is called diastole. The period of contraction is called systole. Diastole is the longer of the two phases so that the heart can rest between contractions. In general, the rate of heartbeat varies inversely with the size of the animal. In elephants it averages 25 beats per minute, in canaries about 1,000. In humans the rate diminishes progressively from birth (when it averages 130) to adolescence but increases slightly in old age; the average adult rate is 70 beats at rest. The rate increases temporarily during exercise, emotional excitement, and fever and decreases during sleep. Rhythmic pulsation felt on the chest, coinciding with heartbeat, is called the apex beat. It is caused by pressure exerted on the chest wall at the outset of systole by the rounded and hardened ventricular wall.

The rhythmic noises accompanying heartbeat are called heart sounds. Normally, two distinct sounds are heard through the stethoscope: a low, slightly prolonged lub (first sound) occurring at the beginning of ventricular contraction, or systole, and produced by closure of the mitral and tricuspid valves, and a sharper, higher-pitched dup (second sound), caused by closure of aortic and pulmonary valves at the end of systole. Occasionally audible in normal hearts is a third soft, low-pitched sound coinciding with early diastole and thought to be produced by vibrations of the ventricular wall. A fourth sound, also occurring during diastole, is revealed by graphic methods but is usually inaudible in normal subjects; it is believed to be the result of atrial contraction and the impact of blood, expelled from the atria, against the ventricular wall.

Heart murmurs may be readily heard by a physician as soft swishing or hissing sounds that follow the normal sounds of heart action. Murmurs may indicate that blood is leaking through an imperfectly closed valve and may signal the presence of a serious heart problem. Coronary heart disease, in which an inadequate supply of oxygen-rich blood is delivered to the myocardium owing to the narrowing or blockage of a coronary artery by fatty plaques, is a leading cause of death worldwide.

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Heart | Structure, Function, Diagram, Anatomy, & Facts | Britannica

Journey to the heart of our being with the cardiovascular system study guide. Aspiring nurses, chart the pulsating rivers of life as you discover the anatomy and dynamics of the bodys powerful pump and intricate vessel networks.

The functions of the heart are as follows:

The cardiovascular system can be compared to a muscular pump equipped with one-way valves and a system of large and small plumbing tubes within which the blood travels.

The modest size and weight of the heart give few hints of its incredible strength.

The heart muscle has three layers and they are as follows:

The heart has four hollow chambers, or cavities: two atria and two ventricles.

The great blood vessels provide a pathway for the entire cardiac circulation to proceed.

The heart is equipped with four valves, which allow blood to flow in only one direction through the heart chambers.

Although the heart chambers are bathed with blood almost continuously, the blood contained in the heart does not nourish the myocardium.

Blood circulates inside the blood vessels, which form a closed transport system, the so-called vascular system.

Except for the microscopic capillaries, the walls of the blood vessels have three coats or tunics.

The major branches of the aorta and the organs they serve are listed next in the sequence from the heart.

Arterial Branches of the Ascending Aorta

The aorta springs upward from the left ventricle of the heart as the ascending aorta.

Arterial Branches of the Aortic Arch

The aorta arches to the left as the aortic arch.

Arterial Branches of the Thoracic Aorta

The aorta plunges downward through the thorax, following the spine as the thoracic aorta.

Arterial Branches of the Abdominal Aorta

Finally, the aorta passes through the diaphragm into the abdominopelvic cavity, where it becomes the abdominal aorta.

Major veins converge on the venae cavae, which enter the right atrium of the heart.

Veins Draining into the Superior Vena Cava

Veins draining into the superior vena cava are named in a distal-to-proximal direction; that is, in the same direction the blood flows into the superior vena cava.

Veins Draining into the Inferior Vena Cava

The inferior vena cava, which is much longer than the superior vena cava, returns blood to the heart from all body regions below the diaphragm.

As the heart beats or contracts, the blood makes continuous round trips- into and out of the heart, through the rest of the body, and then back to the heart- only to be sent out again.

The spontaneous contractions of the cardiac muscle cells occurs in a regular and continuous way, giving rhythm to the heart.

The conduction system occurs systematically through:

In a healthy heart, the atria contract simultaneously, then, as they start to relax, contraction of the ventricles begins.

Cardiac output is the amount of blood pumped out by each side of the heart in one minute. It is the product of the heart rate and the stroke volume.

A fairly good indication of the efficiency of a persons circulatory system can be obtained by taking arterial blood and blood pressure measurements.

Arterial pulse pressure and blood pressure measurements, along with those of respiratory rate and body temperature, are referred to collectively as vital signs in clinical settings.

The right and left sides of the heart work together in achieving a smooth-flowing blood circulation.

Substances tend to move to and from the body cells according to their concentration gradients.

The capacity of the heart for work decreases with age. Older peoples rate is slower to respond to stress and slower to return to normal after periods of physical activity. Changes in arteries occur frequently which can negatively affect blood supply.

Health promotion teaching can include risk detection and reduction for cardiovascular diseases, blood pressure and cholesterol level monitoring, ideal weight maintenance, and a low-sodium diet.

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Cardiovascular System Anatomy and Physiology - Nurseslabs

the insertion of a catheter into a vein or artery and guiding of it into the interior of the heart for purposes of measuring cardiac output, determining the oxygen content of blood in the heart chambers, and evaluating the structural components of the heart. It is indicated whenever it is necessary to establish a precise and definite diagnosis in order to determine whether heart surgery is necessary and to plan the surgical approach.

A, Right-sided heart catheterization. The catheter is inserted into the femoral vein and advanced through the inferior vena cava (or, if into an antecubital or basilic vein, through the superior vena cava), right atrium, and right ventricle and into the pulmonary artery. B, Left-sided heart catheterization. The catheter is inserted into the femoral artery or the antecubital artery. The catheter is passed through the ascending aorta, through the aortic valve, and into the left ventricle. From Ignatavicius and Workman, 2002.

During the initial assessment it is important to find out whether the patient has any allergies. The contrast medium used contains iodide salts; if a patient is allergic to iodine or seafood, a contrast medium that does not contain iodine must be used, or antihistamines must be administered before the procedure. A mild tranquilizer or hypnotic may be given just before the procedure to help the patient relax, but a general anesthetic is not used. Patients need to know that they must be awake and cooperative during the procedure. They will be asked to stay in a certain position, cough, breathe deeply, and possibly exercise so that the heart's response to an increased workload can be evaluated. They should be reassured that the laboratory staff is ready and equipped to handle any emergency should the need arise.

Ideally, preprocedure visits by the physician and a member of the staff in the cardiac catheterization laboratory will provide patients with the information they need about the procedure, its purpose, and potential complications. However, because of anxiety the patient may not be able to assimilate the information and will have many questions not asked at the time of the visits. It is then the responsibility of the floor nurses to answer questions as honestly as they can and to provide emotional support and reassurance.

After the procedure the vital signs are checked periodically. It is especially important to check the pulses distal to the insertion site every half-hour for three hours, or as often as required by protocol, to be sure there has been no clotting and obstruction of a blood vessel. The insertion site dressing is changed as needed and the site inspected for signs of infection. Thirst and diuresis are expected because of the effect of the dye used in the procedure. The patient should be encouraged to drink fluids to prevent hypotension and hasten excretion of the dye, which is potentially nephrotoxic. Mild discomfort also is expected and should respond to the prescribed analgesic. If the patient experiences severe pain the physician should be notified.

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Cardiac | definition of cardiac by Medical dictionary

Research Progress on the Mechanisms of Endogenous Neural Stem Cell Differentiation in Spinal Cord Injury Repair  Frontiers

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Research Progress on the Mechanisms of Endogenous Neural Stem Cell Differentiation in Spinal Cord Injury Repair - Frontiers

Bone marrow mesenchymal stem cells (BM-MSCs) are a vital component of regenerative medicine due to their ability to differentiate into various cell types and modulate immune responses. Their therapeutic potential has led to extensive research on their biological properties, mechanisms of action, and clinical applications.

Understanding BM-MSCs requires examining their microenvironment, distinguishing characteristics, isolation techniques, differentiation pathways, and how they compare to other stem cell types.

BM-MSCs originate from the mesodermal germ layer during embryonic development and persist into adulthood for tissue maintenance and repair. Within the bone marrow, they coexist with hematopoietic stem cells (HSCs) and other stromal components, contributing to the marrow niches structure and function. Their distribution is not uniform, with higher concentrations in trabecular-rich regions such as the iliac crest, femur, and sternum. These sites provide a supportive environment where BM-MSCs interact with the extracellular matrix, soluble factors, and neighboring cells to regulate proliferation and differentiation.

The bone marrow microenvironment is a specialized niche that governs BM-MSC behavior through biochemical and mechanical cues. It consists of an extracellular matrix composed of collagen, fibronectin, and laminin, which provides structural support and modulates adhesion. Oxygen tension in the marrow is lower than in peripheral tissues, with hypoxic conditions (1% to 7% oxygen) helping maintain BM-MSC quiescence and stemness. Hypoxia-inducible factors (HIFs) mediate responses to low oxygen levels, promoting genes involved in self-renewal and metabolic adaptation.

Cellular interactions further shape BM-MSC function. Crosstalk with endothelial cells, osteoblasts, and pericytes influences their role in supporting hematopoiesis and tissue homeostasis. Endothelial cells secrete vascular endothelial growth factor (VEGF), enhancing BM-MSC survival and migration. Osteoblasts provide osteogenic signals that prime BM-MSCs for differentiation into bone-forming cells. Pericytes, which share similarities with BM-MSCs, contribute to vascular stability and regulate stem cell fate.

BM-MSCs are defined by a unique set of surface markers that distinguish them from other stromal and hematopoietic populations. Unlike HSCs, BM-MSCs lack CD34, CD45, and CD14, which are associated with blood cell lineages. Instead, they express CD73, CD90, and CD105, as established by the International Society for Cell and Gene Therapy (ISCT). These markers facilitate identification, isolation, and functional characterization.

CD73, also known as ecto-5-nucleotidase, catalyzes the conversion of extracellular AMP into adenosine, modulating microenvironmental signals. CD90, or Thy-1, is a glycoprotein involved in cell-cell and cell-matrix interactions, influencing BM-MSC proliferation and differentiation. CD105, or endoglin, serves as a co-receptor for transforming growth factor-beta (TGF-), maintaining BM-MSC multipotency and guiding lineage commitment.

Additional markers refine BM-MSC characterization. CD146, a pericyte-associated marker, is linked to heightened clonogenic potential. STRO-1, an early mesenchymal progenitor marker, correlates with enhanced osteogenic differentiation but diminishes with cell expansion. CD271, or low-affinity nerve growth factor receptor (LNGFR), has been proposed for isolating highly pure BM-MSC populations with superior regenerative properties.

Isolating and expanding BM-MSCs are critical for research and clinical applications. Various techniques selectively extract BM-MSCs while minimizing contamination from hematopoietic and other stromal cells.

Density gradient centrifugation separates mononuclear cells from other bone marrow components based on cell density. Ficoll-Paque and Percoll are commonly used media that enrich BM-MSCs by allowing lower-density mononuclear cells to form a distinct layer after centrifugation. This method is simple and cost-effective but does not exclusively isolate BM-MSCs, as the mononuclear fraction contains hematopoietic cells. To improve purity, plastic adherence-based selection is often employed, where BM-MSCs attach to tissue culture plastic while non-adherent cells are removed. However, this approach has limitations, including variability in yield and potential contamination.

Fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) isolate BM-MSCs based on surface marker expression. FACS uses fluorescently labeled antibodies targeting BM-MSC markers such as CD73, CD90, and CD105, allowing high-purity selection through laser-based detection. MACS employs magnetic beads conjugated to antibodies, enabling rapid and scalable cell separation. While FACS provides greater resolution, it requires specialized equipment and is time-intensive. MACS, though less precise, is more accessible and suitable for large-scale cell enrichment.

Enzymatic digestion methods use proteolytic enzymes such as collagenase and trypsin to break down the extracellular matrix and release BM-MSCs. Collagenase digestion is commonly used to degrade collagen-rich structures while preserving viability. Trypsin, often combined with other enzymes, aids in cell detachment. While enzymatic dissociation enhances cell recovery, excessive enzyme exposure can compromise viability and surface marker integrity. This method is often combined with culture-based selection for further enrichment.

BM-MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes. This process is governed by transcription factors and environmental cues that guide lineage commitment. The surrounding microenvironment, including mechanical forces and biochemical signals, influences differentiation outcomes.

Osteogenic differentiation is driven by RUNX2, which activates genes responsible for bone matrix deposition. Calcium, phosphate, and bone morphogenetic proteins (BMPs) reinforce osteogenesis by enhancing mineralization. Chondrogenic differentiation is regulated by SOX9, which promotes cartilage-specific proteins such as aggrecan and type II collagen. Hypoxic conditions sustain chondrocyte-like characteristics. Adipogenic differentiation is controlled by PPAR and C/EBP, which drive lipid accumulation and adipocyte-specific gene expression.

BM-MSC differentiation is regulated by signaling pathways that govern self-renewal, proliferation, and lineage commitment. The Notch, Wnt, and BMP pathways play key roles in directing fate decisions.

The Notch pathway influences BM-MSC proliferation and differentiation through cell-to-cell communication. Activation occurs when Notch ligands bind to receptors, triggering cleavage and release of the Notch intracellular domain (NICD). NICD translocates to the nucleus and modulates gene expression. Notch signaling maintains BM-MSCs in an undifferentiated state by suppressing osteogenic and adipogenic differentiation while promoting chondrogenesis. Sustained Notch activation enhances cartilage formation by upregulating SOX9, while inhibition facilitates osteogenesis by relieving suppression on RUNX2.

The Wnt signaling cascade affects BM-MSC fate through canonical and non-canonical pathways. In the canonical pathway, Wnt ligands bind to Frizzled receptors, stabilizing -catenin, which activates osteogenic genes. This pathway promotes bone formation by enhancing RUNX2 expression and matrix mineralization. The non-canonical pathway, independent of -catenin, regulates cytoskeletal organization and migration. Canonical Wnt signaling favors osteogenesis while inhibiting adipogenesis by suppressing PPAR, maintaining a balance in BM-MSC differentiation.

Bone morphogenetic proteins (BMPs) regulate BM-MSC differentiation, particularly in bone and cartilage formation. BMP ligands bind to receptors, triggering SMAD phosphorylation and transcriptional regulation. BMP2 and BMP7 induce osteogenesis by upregulating RUNX2 and enhancing extracellular matrix deposition. BMP signaling also synergizes with SOX9 to promote chondrogenesis. While BMPs favor skeletal differentiation, excessive signaling can lead to aberrant ossification.

BM-MSCs differ from other stem cell populations in differentiation potential, immunomodulatory effects, and tissue origin. Unlike HSCs, which primarily generate blood cells, BM-MSCs contribute to mesodermal-derived tissues such as bone, cartilage, and adipose. Their ability to differentiate into multiple skeletal and connective tissue types makes them valuable for regenerative applications.

Compared to embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), BM-MSCs have a more restricted differentiation capacity, as they do not generate cells from all three germ layers. However, this reduces the risk of teratoma formation, a concern with pluripotent stem cell-based therapies. BM-MSCs are also more accessible and ethically uncontroversial, as they can be harvested from adult bone marrow. Their immunomodulatory properties further distinguish them, as they modulate immune responses through cytokine secretion and direct interactions, making them useful in inflammatory and autoimmune conditions.

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Bone Marrow Mesenchymal Stem Cells: Key Insights and Functions

In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking  Nature

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In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking - Nature

New Gene Therapy Reverses Three Diseases With Shots to the Bloodstream  SingularityHub

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New Gene Therapy Reverses Three Diseases With Shots to the Bloodstream - SingularityHub

Newborn Mice May Hold the Key to Simpler Gene Therapy  the-scientist.com

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Newborn Mice May Hold the Key to Simpler Gene Therapy - the-scientist.com

World's first therapy to reverse spinal cord injury enters human trial  New Atlas

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World's first therapy to reverse spinal cord injury enters human trial - New Atlas

Parkinson's disease (PD) develops from the gradual loss of neurons that produce dopamine, which is critical to your movement, mood and motivation. The quest for effective treatments that address dopamine loss has included stem cell research using tissue that can be transformed into dopamine neurons. However, previous stem cell studies showed mixed results for Parkinsons and attempts at transplanting stem cells into the brain have fallen short.

A new avenue of possibilities has emerged with induced pluripotent stem (iPS) and human embryonic stem (hES) cells. These types of stem cells have the unique ability to develop into any cell type in the body, offering a potentially limitless source for generating the dopamine neurons lost in Parkinson's.

Scientists have been exploring the potential of these cells to create safe and effective therapies that could one day alleviate Parkinsons symptoms. Interestingly, the development of iPS cells earned Shinya Yamanaka the Nobel Prize in Physiology or Medicine in 2012. This type of stem cell is derived directly from adult tissue and is not associated with embryonic stem cells.

Two new clinical trials (Phase I and II), both published in Nature, evaluated the safety and potential benefits of transplanting early-stage dopamine-producing cells derived from specific types of stem cells.

One study, conducted in Japan, explored iPS cells, which were derived from the blood of a healthy adult.

The other study, conducted in the U.S. and Canada, used a human embryonic stem (hES) cell line developed in 1998.

These trials involved a total of 19 people living with Parkinson's, with seven enrolled in the iPS study and 12 in the hES study.

Each participant received a transplantation of cells on the path to becoming dopaminergic neurons, derived from either iPS or hES cells, directly into a part of the brain involved in movement (called the putamen). Both studies randomly divided participants in half, with half receiving a higher dose of cells, and half receiving a lower dose of cells. All participants received immunosuppressive medication, which reduces the activity of the body's immune system to prevent it from attacking the new dopamine-producing cells.

The primary focus of these trials was to monitor the safety of the approach and to carefully track any problems that occurred 18-24 months after transplantation.

Encouragingly, the results showed no serious adverse events in either study directly linked to the cell transplantation. Magnetic resonance imaging (MRI) scans showed no signs of tumors forming from the transplanted cells. Additionally, there were no issues in either study with involuntary movements (dyskinesias) induced by the transplanted cells, which has been a concern with previous cell studies.

Beyond safety, the researchers also observed any changes in the participants' symptoms and their brain's ability to produce dopamine. Most participants continued their PD medications.

For the participants receiving cells from iPS cells, among the six participants who underwent a thorough evaluation (one dropped out due to a COVID-19 infection), most showed notable improvements in their movement symptoms.

Four participants showed improvement on a standard scale used to assess Parkinson's movement symptoms when they were off their medication and five participants had improvements in the PD measurement scale when they were on medication.

Furthermore, brain scans using a specialized tracer that detects dopamine production revealed an average increase of 44.7% in dopamine activity in a key brain region called the putamen, with even greater increases seen in those who received a higher dose of the transplanted cells.

While other measures showed more subtle changes, the overall findings are promising.

For the participants receiving cells from hES cells, the researchers also saw signs that the therapy might be working. Brain scans taken 18 months after the transplant showed:

Increased activity in the putamen, suggesting that the transplanted cells had survived and were potentially functioning.

Furthermore, those who received the higher dose of the cell therapy showed an average improvement of 23 points on their PD measurement scale scores when they were off their regular medication.

While these are early results that need to be replicated, they offer a glimpse into a potential new way to treat Parkinson's and pave the way for larger studies to confirm these findings.

Two studies enrolled 19 people with Parkinsons and transplanted stem cell-derived progenitor cells on the path to becoming dopaminergic neurons directly into a part of their brain called the putamen.

Both studies used established stem cell lines, meaning no new tissue donation was involved.

Both studies observed an improvement in Parkinson's movement symptoms in most participants.

Brain scans showed increased activity in the area of the brain after the cells were transplanted, suggesting that the cells survived and were potentially functioning.

There were no tumors formed or other issues linked to the cells 18 months after transplantation.

Overall, the main takeaway from these studies is that it appears stem cell research can be conducted safely without major adverse effects. Additionally, the studies also suggest the possibility that stem cell treatments may be able to help people with PD manage symptoms. However, more research is needed to confirm that this treatment is safe and effective, particularly in larger and longer-term studies.

In addition, while these studies may have just re-opened the door for more PD-related stem cell research, it is important to know that potential stem cell treatments are linked to PD movement symptoms relief, not non-movement symptoms. In summary, these studies will most likely kick-start new research surrounding stem cell therapy as a promising treatment for Parkinsons.

This breakthrough offers a new line of research hope for people living with Parkinsons today. It has been a long time since stem cell-based therapies have been seen as a safe treatment option with promise for symptom management. However, stem cell therapies are not yet a proven treatment for PD.

Given the promising results of these iPS cell or hES cell studies, similar studies will most likely be on the horizon. If you find a stem cell study of interest, talk to your PD doctor about the study, and share the study protocol and informed consent for him/her to review. It is a red flag if a study does not provide either one of these documents. Importantly, there should never be a fee or cost to participate in a clinical trial, including stem cell trials and studies.

This article is part of our Science News series. The studies mentioned in this article are conducted by a third party and are not funded by the Parkinson's Foundation.

The Parkinsons Foundation believes in empowering the Parkinsons community through education. Learn more about PD and the topics in this article through our below resources, or by calling our free Helpline at 1-800-4PD-INFO (1-800-473-4636) for answers to your Parkinsons questions.

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Two New Trials Explore Stem-Cell Therapy for Parkinson's

Drug targeting on skin cancer stem cell niche. The figure depicts the...  ResearchGate

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Drug targeting on skin cancer stem cell niche. The figure depicts the... - ResearchGate

Want to look young and be healthy? Try these five Harvard nutritionist-approved foods to boost stem cells for organ and skin repair  Times of India

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Want to look young and be healthy? Try these five Harvard nutritionist-approved foods to boost stem cells for organ and skin repair - Times of India

U achieves first successful allogenic stem cell transplant using graft from deceased donor  The University of Utah

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U achieves first successful allogenic stem cell transplant using graft from deceased donor - The University of Utah

Delivery of bone marrow mesenchymal stem cell-derived exosomes into fibroblasts attenuates intestinal fibrosis by weakening its transdifferentiation via the CCN2-TGF- axis  Nature

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Delivery of bone marrow mesenchymal stem cell-derived exosomes into fibroblasts attenuates intestinal fibrosis by weakening its transdifferentiation...

Gene therapy: a first of its kind at Sainte-Justine Hospital  CityNews Montreal

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Gene therapy: a first of its kind at Sainte-Justine Hospital - CityNews Montreal

Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool  Nature

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Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool - Nature

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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Hematopoietic stem cell - Wikipedia

A step closer to the confident production of blood stem cells for regenerative medicine  Medical Xpress

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A step closer to the confident production of blood stem cells for regenerative medicine - Medical Xpress

Circadian rhythm and aryl hydrocarbon receptor crosstalk in bone marrow adipose tissue and implications in leukemia  Nature

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Circadian rhythm and aryl hydrocarbon receptor crosstalk in bone marrow adipose tissue and implications in leukemia - Nature

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