Clinical uses of mesenchymal stem cells

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Adult mesenchymal stem cell s are being used by researchers in the fields of regenerative medicine and tissue engineering to artificially reconstruct human tissue which has been previously damaged. Mesenchymal stem cells are able to differentiate, or mature from a less specialized cell to a more specialized cell type, to replace damaged tissues in various organs. [1] [2] [3]

Contents

Isolation of mesenchymal stem cells

Obtaining mesenchymal stem cells from the bone marrow

In the research process of expanding the therapeutic uses of mesenchymal stem cells, they are grown in laboratories or grown using medication to stimulate new cell growth within the human body. In mesenchymal stem cell therapy, most of the cells are extracted from the adult patient’s bone marrow  [2] [3] Mesenchymal stem cells can be obtained via a procedure called bone marrow aspiration. A needle is inserted into the back of the patients hip bone and cells are removed to be grown under controlled in vitro conditions in a lab. Over a course of two or three weeks, the cells will multiply and differentiate into specialized cells. The number of fully differentiated cells and their phenotype can be influenced in three ways. The first one is by varying the initial seed density in the culture medium. The second is by changing the conditions of the medium. The third is by the addition of additives such as proteins or growth hormones to the culture medium to promote growth. The mature cells are then harvested and injected back into the patient through local delivery or systemic infusion.

Isolation efficiency

Isolation of mesenchymal stem cells from the bone marrow requires an invasive procedure. Mesenchymal stem cells can also be isolated from birth-associated tissues such as the umbilical cord without the need for an invasive surgical procedure. Differences in isolation efficiency are attributed to the availability, condition, and age of the donor tissue. An issue related to culturing mesenchymal stem cells is the insufficient number of cells that can be produced. [1] [3] During long-term culture, mesenchymal stem cells age, lose their ability to differentiate, and have a higher chance to undergo malignant transformation. [4] [5]

Therapeutic properties

Mesenchymal stem cells possess many properties that are ideal for the treatment of inflammatory and degenerative diseases. [6] [7] They can differentiate into many cell types including bone, fat, and muscle which allow them to treat a large range of disorders. [8] [9] They possess natural abilities to detect changes in their environment, such as inflammation. They can then induce the release of bioactive agents and the formation of progenitor cells in response to these changes. [9] Mesenchymal stem cells have also been shown to travel to sites of inflammation far from the injection site. [7] [10] [11]

Mesenchymal stem cells can be easily extracted through well-established procedures such as bone marrow aspiration. [7] Also, transplanted mesenchymal stem cells pose little risk for rejection as they are derived from the patients own tissue, so are genetically identical, however graft versus host disease is a possibility, where the cells change enough while outside the patient's body that the immune system recognizes them as foreign and can attempt to reject them. This can lead to symptoms such as itchiness, sensitive/raw skin and shedding or dry skin. . [6]

Advantages over embryonic stem cells

Several different forms of stem cells have been identified and studied in the field of regenerative medicine. One of the most extensively studied stem cell types are embryonic stem cells, which possess many of the same therapeutic properties as mesenchymal stem cells, including the ability to self-regenerate and differentiate into a number of cell lineages. [8] Their therapeutic abilities have been demonstrated in a number of studies of autoimmunity and neurodegeneration in animal models. [8] [7] [10] [12]

However, their therapeutic potential has been largely limited by several key factors. [7] Injected embryonic stem cells have been shown to increase the risk for tumor formation in the host patient. [8] [7] [12] Also, the host’s immune system may reject injected embryonic stem cells and thus eliminate their therapeutic effects. [7] Finally, research has been largely limited due to the ethical issues that surround their controversial procurement from fertilized embryos. [8] [12]

Safety concerns

Human mesenchymal stem cell therapy is limited due to variation in individual response to treatment and the high number of cells needed for treatment. [2] More long-term studies are needed to ensure the safety of mesenchymal stem cells. In previous studies which observed the safety of clinical mesenchymal stem cell use, no serious side effects were noted. [3] However, there have been some cases where there were both improvement and toxicity inflicted on the targeted organ, as well as cases where treatment of mesenchymal stem cells did not show improvement of function at all. In addition, there is a risk of tumorigenesis after stem cell transplantation due to the ability of stem cells to proliferate and resist apoptosis. Genetic mutations in stem cells as well as conditions at target tissue may result in formation of a cancerous tumor. Studies have shown that bone marrow mesenchymal stem cells can migrate to solid tumors and promote tumor growth in various cancer models [13] [14] [15] [16] through the secretion of proangiogenic factors.

Treated disorders

Mesenchymal stem cells have been used to treat a variety of disorders including cardiovascular diseases, spinal cord injury, bone and cartilage repair, and autoimmune diseases.

Treatment for multiple sclerosis

A vast amount research has been conducted in recent years for the use of mesenchymal stem cells to treat multiple sclerosis. [17] [18] This form of treatment for the disease has been tested in many studies of experimental allergic encephalomyelitis, the animal model of multiple sclerosis, and several published and on-going phase I and phase II human trials. [8] [6] [9] [12]

Treatment requirements

Current treatments are unable to prevent the accumulation of irreversible damage to the central nervous system. [11] Patients with multiple sclerosis experience two major forms of damage, one from on-going autoimmune induced processes and the other to natural pair mechanisms. [6] Therefore, an ideal treatment must possess both immunomodulating properties to control irregular autoimmune responses and regenerative properties to stimulate natural repair mechanisms that can replace damaged cells. [8] [6]

Therapeutic mechanisms

The exact therapeutic mechanisms of mesenchymal stem cells in the treatment of multiple sclerosis are still very much up to debate among stem cell researchers. [8] [6] [9] Some of the suggested mechanisms are immunomodulation, neuroprotection, and neuroregeneration. [6]

  • Immunomodulation
Mesenchymal stem cells can induce the release of bioactive agents such as cytokines that can inhibit autoimmune responses. [8] [6] In patients with multiple sclerosis, autoreactive lymphocytes such as T and B cells cause damage to the central nervous system by attacking myelin proteins. Myelin proteins make up the myelin sheath that functions in protecting nerve axons, maintaining structural integrity, and enabling the efficient transmission of nerve impulses. [11] By suppressing the unregulated proliferation of T and B cells, mesenchymal stem cells can potentially minimize and control on-going damage to the central nervous system. [8] [9] [11]
Mesenchymal stem cells can also stimulate the maturation of antigen presenting cells. [6] [9] Antigen presenting cells trigger the immune system to produce antibodies that can destroy potentially harmful agents. [6] This property allows mesenchymal stem cells to actively contribute to neutralizing harmful autoreactive T and B cells. [8]
  • Neuroprotection
Mesenchymal stem cells can promote neuroprotection in the central nervous systems which may prevent the progression of chronic disability. [11] The mechanisms include inhibiting apoptosis of healthy cells and preventing gliosis, the formation of a glial scar. [6] [11] They can also stimulate local progenitor cells to produce replacement cells for rebuilding the myelin sheath. [6]
  • Neuroregeneration
The regenerative abilities of the central nervous system are greatly decreased in adults, impairing its ability to regenerate axons following injury. [11] In addition to this natural limitation, patients with multiple sclerosis exhibit an even greater decrease in neuroregeneration along with enhanced neurodegeneration. [8] [11] [17] [18] They experience a significant decrease in the number of neural stem cells which produce progenitor cells necessary for normal maintenance and function. [6] [9] Decreases in the neural stem cells results in severe damage to the ability of the central nervous system to repair itself. [9] This process results in the amplified neurodegeneration exhibited in patients with multiple sclerosis. [6] [9]
Mesenchymal stem cells have the ability to stimulate neuroregeneration by differentiating into neural stem cells in response to inflammation. The neural stem cells can then promote the repair of damaged axons and create replacement cells for the damaged tissue. [11] [19] Regeneration and repair of damaged axons has been shown to occur naturally and spontaneously in the central nervous system. This shows that it is an environment capable of unassisted, natural healing. [19] Mesenchymal stem cells contribute to this regenerative environment by releasing bioactive agents that inhibit apoptosis and thus create an ideal regenerative environment. [6]

Cardiovascular Diseases

Mesenchymal stem cells are able to alleviate heart fiber injury and prevent cardiac muscle cell death in mouse models of myocardial infarction, or heart attack, and prevent its further development. [20] [21] [22] They can migrate to areas of inflammation and decrease infarction and improve cardiac function.

Brain Disorders

Mesenchymal stem cells have the potential to treat brain strokes as well. They can secrete factors that stimulate the function of brain cells, leading to neuron formation, blood vessel formation, and improved synaptic plasticity. They can also differentiate into neurons and neural cells to replace damaged cells. Behavioral tests performed in mouse models demonstrated a return back to normal brain function after treatment with mesenchymal stem cells. [23] [24]

Liver Diseases

Mesenchymal stem cells can also regenerate and repair damaged liver cells. In mouse models of liver fibrosis, mesenchymal stem cells delivered to the liver were shown to improve liver function by reducing inflammation and necrosis and inducing hepatocyte regeneration. [25] [26] [27]

Related Research Articles

<span class="mw-page-title-main">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

<span class="mw-page-title-main">Bone marrow</span> Semi-solid tissue in the spongy portions of bones

Bone marrow is a semi-solid tissue found within the spongy portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production. It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Stromal cell-derived factor 1</span> Mammalian protein found in Homo sapiens

The stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the CXCL12 gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types. Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the chemokine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1. The chemokines are characterized by the presence of 4 conserved cysteines that form 2 disulfide bonds. They can be classified into 2 subfamilies. In the CC subfamily, the cysteine residues are adjacent to each other. In the CXC subfamily, they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group. CXCL12 signaling has been observed in several cancers. The CXCL12 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Regenerative medicine</span> Field of medicine involved in regenerating tissues

Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". This field holds the promise of engineering damaged tissues and organs by stimulating the body's own repair mechanisms to functionally heal previously irreparable tissues or organs.

<span class="mw-page-title-main">Cell therapy</span> Therapy in which cellular material is injected into a patient

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

<span class="mw-page-title-main">Adult stem cell</span> Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition. As of 2016, the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone-marrow transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.

<span class="mw-page-title-main">Osteonecrosis of the jaw</span> Medical condition

Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws. Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature.

Mesenchymal stem cells (MSCs) are multipotent cells found in multiple human adult tissues including bone marrow, synovial tissues, and adipose tissues. Since they are derived from the mesoderm, they have been shown to differentiate into bone, cartilage, muscle, and adipose tissue. MSCs from embryonic sources have shown promise scientifically while creating significant controversy. As a result, many researchers have focused on adult stem cells, or stem cells isolated from adult humans that can be transplanted into damaged tissue.

Amniotic stem cells are the mixture of stem cells that can be obtained from the amniotic fluid as well as the amniotic membrane. They can develop into various tissue types including skin, cartilage, cardiac tissue, nerves, muscle, and bone. The cells also have potential medical applications, especially in organ regeneration.

<span class="mw-page-title-main">Mesenchymal stem cell</span> Multipotent, non-hematopoietic adult stem cells present in multiple tissues

Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes.

Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor or unipotent – (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

A Muse cell is an endogenous non-cancerous pluripotent stem cell. They reside in the connective tissue of nearly every organ including the umbilical cord, bone marrow and peripheral blood. They are collectable from commercially obtainable mesenchymal cells such as human fibroblasts, bone marrow-mesenchymal stem cells and adipose-derived stem cells. Muse cells are able to generate cells representative of all three germ layers from a single cell both spontaneously and under cytokine induction. Expression of pluripotency genes and triploblastic differentiation are self-renewable over generations. Muse cells do not undergo teratoma formation when transplanted into a host environment in vivo. This can be explained in part by their intrinsically low telomerase activity, eradicating the risk of tumorigenesis through unbridled cell proliferation. They were discovered in 2010 by Mari Dezawa and her research group. Clinical trials for acute myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, amyotrophic lateral sclerosis, acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection, are conducted by Life Science Institute, Inc., a group company of Mitsubishi Chemical Holdings company. Physician-led clinical trial for neonatal hypoxic-ischemic encephalopathy was also started. The summary results of a randomized double-blind placebo-controlled clinical trial in patients with stroke was announced.

Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.

Spinal cord injury research seeks new ways to cure or treat spinal cord injury in order to lessen the debilitating effects of the injury in the short or long term. There is no cure for SCI, and current treatments are mostly focused on spinal cord injury rehabilitation and management of the secondary effects of the condition. Two major areas of research include neuroprotection, ways to prevent damage to cells caused by biological processes that take place in the body after the injury, and neuroregeneration, regrowing or replacing damaged neural circuits.

<span class="mw-page-title-main">Shimon Slavin</span> Israeli professor of medicine

Shimon Slavin, M.D., is an Israeli professor of medicine. Slavin pioneered the use of immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation for the cure of hematological malignancies and solid tumors, and using hematopoietic stem cells for induction of transplantation tolerance to bone marrow and donor allografts.

Craniofacial regeneration refers to the biological process by which the skull and face regrow to heal an injury. This page covers birth defects and injuries related to the craniofacial region, the mechanisms behind the regeneration, the medical application of these processes, and the scientific research conducted on this specific regeneration. This regeneration is not to be confused with tooth regeneration. Craniofacial regrowth is broadly related to the mechanisms of general bone healing.

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