Mesenchymal stem cell
Mesenchymal stem cell | |
---|---|
electron micrograph of a mesenchymal stem cell displaying typical ultrastructural characteristics. | |
Details | |
Identifiers | |
Latin | cellula mesenchymatica praecursoria |
MeSH | D059630 |
TH | H2.00.01.0.00008 |
Anatomical terms of microanatomy] |
Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells, are
Structure
Definition
Mesenchymal stem cells (MSCs), a term first named (1991) by Arnold I. Caplan at Case Western Reserve University,
- Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells.[6]
- Stromal cells are connective tissue cells that form the supportive structure in which the functional cells of the tissue reside. While this is an accurate description for one function of MSCs, the term fails to convey the relatively recently discovered roles of MSCs in the repair of tissue.[7]
- The term encompasses multipotent cells derived from other non-marrow tissues, such as placenta,[8] umbilical cord blood, adipose tissue, adult muscle, corneal stroma,[9] or the dental pulp of deciduous (baby) teeth.[10] The cells do not have the capacity to reconstitute an entire organ.
Morphology
The cell body contains a large, round
Classification
The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs. A cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology. In fact, some argue that MSCs and fibroblasts are functionally identical.
Location in the body
MSCs are found throughout the human body.
Bone marrow
Bone marrow was the original source of MSCs,[15] and is still the most frequently utilized source. These bone marrow stem cells do not contribute to the formation of blood cells, and so do not express the hematopoietic stem cell marker CD34. They are sometimes referred to as bone marrow stromal stem cells.[16]
Cord cells
The youngest and most primitive MSCs may be obtained from umbilical cord tissue, namely Wharton's jelly and the umbilical cord blood. However, MSCs are found in much higher concentration in the Wharton's jelly compared to cord blood, which is a rich source of hematopoietic stem cells. The umbilical cord is available after a birth. It is normally discarded, and poses no risk for collection. These MSCs may prove to be a useful source of MSCs for clinical applications, due to their primitive properties and fast growth rate.[17]
These cells have several advantages over bone-marrow-derived MSCs. Adipose-tissue-derived MSCs (AdMSCs), in addition to being easier and safer to isolate than bone-marrow-derived MSCs, can be obtained in larger quantities.[15][18]
Adipose tissue
Adipose-tissue-derived MSCs (AdMSCs), in addition to being easier and safer to isolate than bone-marrow-derived MSCs, can be obtained in larger quantities.
Molar cells
The developing tooth bud of the mandibular third molar is a rich source of MSCs. While they are described as multipotent, it is possible that they are pluripotent. They eventually form enamel, dentin, blood vessels, dental pulp, and nervous tissues. These stem cells are capable of differentiating into
Amniotic fluid
Stem cells are present in amniotic fluid. As many as 1 in 100 cells collected during amniocentesis are pluripotent mesenchymal stem cells.[19]
Function
Differentiation capacity
MSCs have a great capacity for self-renewal while maintaining their multipotency. Recent work suggests that β-catenin, via regulation of EZH2, is a central molecule in maintaining the "stemness" of MSC's.[20] The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes and chondrocytes as well as myocytes.
MSCs have been seen to even differentiate into neuron-like cells,[21] but doubt remains about whether the MSC-derived neurons are functional.[22] The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical;[23] and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture.[24] Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.[citation needed]
Immunomodulatory effects
MSCs have an effect on innate and specific immune cells, and research has shown an ability to suppress tumor growth.
MSCs have an effect on macrophages, neutrophils, NK cells, mast cells and dendritic cells in innate immunity. MSCs are able to migrate to the site of injury, where they polarize through PGE2 macrophages in M2 phenotype which is characterized by an anti-inflammatory effect.[30] Further, PGE2 inhibits the ability of mast cells to degranulate and produce TNF-α.[31][32] Proliferation and cytotoxic activity of NK cells is inhibited by PGE2 and IDO. MSCs also reduce the expression of NK cell receptors - NKG2D, NKp44 and NKp30.[33] MSCs inhibit respiratory flare and apoptosis of neutrophils by production of cytokines IL-6 and IL-8.[34] Differentiation and expression of dendritic cell surface markers is inhibited by IL-6 and PGE2 of MSCs.[35] The immunosuppressive effects of MSC also depend on IL-10, but it is not certain whether they produce it alone, or only stimulate other cells to produce it.[36]
MSC expresses the adhesion molecules VCAM-1 and ICAM-1, which allow T-lymphocytes to adhere to their surface. Then MSC can affect them by molecules which have a short half-life and their effect is in the immediate vicinity of the cell.[27] These include nitric oxide,[37] PGE2, HGF,[38] and activation of receptor PD-1.[39] MSCs reduce T cell proliferation between G0 and G1 cell cycle phases[40] and decrease the expression of IFNγ of Th1 cells while increasing the expression of IL-4 of Th2 cells.[41] MSCs also inhibit the proliferation of B-lymphocytes between G0 and G1 cell cycle phases.[39][42]
Antimicrobial properties
MSCs produce several
Clinical significance
Mesenchymal stem cells can be activated and mobilized in reaction to injury and infection. As of May 2023, ClinicalTrials.gov lists more than 1,100 studies featuring MSCs[48] for more than 920 conditions.
Autoimmune disease
Clinical studies investigating the efficacy of mesenchymal stem cells in treating diseases are in clinical development around the world, particularly treating
Other diseases
Many of the early clinical successes using intravenous transplantation came in systemic diseases such as graft versus host disease and sepsis. Direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.[51]
Further studies into the mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair.[52][53]
Research
The majority of modern culture techniques still take a colony-forming unit-fibroblasts (CFU-F) approach, where raw unpurified bone marrow or ficoll-purified bone marrow
Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1.[55] STRO-1+ cells are generally more homogenous and have higher rates of adherence and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs are not clear.[56]
Methods of immunodepletion using such techniques as MACS have also been used in the negative selection of MSCs.[57]
The supplementation of basal media with fetal bovine serum or human platelet lysate is common in MSC culture. Prior to the use of platelet lysates for MSC culture, the pathogen inactivation process is recommended to prevent pathogen transmission.[58]
New research titled Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques[59] Various chemicals and methods including low level laser irradiation have been used to increase proliferation of stem cell.[60]
History
Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s.[61][62] In 1970, Arnold Caplan identified certain conditions by which mesodermal cells differentiate into cartilage or myogenic (muscle) tissue and bone.[63]
An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues.[64][65] In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f).
Subsequent experimentation revealed the plasticity of marrow cells and how their fate is determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as
The first clinical trials of MSCs were completed by Osiris Therapeutics in 1995 when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment.[66] The first regulatory approvals for MSCs were granted conditional approval in 2012 in Canada and New Zealand for treating Graft vs. Host Disease (GvHD) and, subsequently, in Japan to treat Crohn’s Disease-related fistula.[67]
Since then, more than 1,000 clinical trials have been conducted to treat numerous conditions.[68]
Controversies
The term "mesenchymal stem cells" and what constitutes the most scientifically correct meaning for the MSC initialism, has been debated for years. Most mesenchymal cell or "MSC" preps only contain a minority fraction of true multipotent stem cells, with most cells being stromal in nature. Caplan proposed rephrasing MSCs to emphasize their role as "medicinal signaling cells."[69] Within the stem cell field, the shorthand "MSC" has most commonly now come to refer to "mesenchymal stromal/stem cells" because of the heterogeneous nature of the cellular preparations.
There is also growing concern about the marketing and application of unapproved MSCs and mesenchymal stem cells that lack rigorous data to back up these clinical uses into patients by for-profit clinics.[70][71]
See also
- Bone marrow
- Fibroblast
- Intramembranous ossification
- Mesenchyme
- Multipotency
- Cord lining
- Marrow Adipose Tissue (MAT)
- List of human cell types derived from the germ layers
References
- S2CID 214523766.
- PMID 24561556.
- PMID 27516776.
- PMID 28452204.
- PMID 18397751.
- .
- PMID 22253772.
- PMID 22546280.
- PMID 22736610.
- ^ PMID 25447379.
- ISBN 978-0-914168-88-1.
- PMID 2071617.
- PMID 22458957.
- PMID 16923606.
- ^ PMID 22468918.
- PMID 15925588.
- S2CID 202731274.
- PMID 18593609.
- ^ "What is Cord Tissue?". CordAdvantage.com. 30 October 2018.
- PMID 32022326.
- S2CID 47162269.
- PMID 19272520.
- S2CID 16109483.
- PMID 24397850.
- S2CID 248485831.
- S2CID 206878089.
- ^ PMID 20130212.
- PMID 22542159.
- PMID 27671847.
- PMID 19772890.
- PMID 21255158.
- PMID 16432506.
- PMID 16239427.
- S2CID 32230553.
- PMID 15692068.
- PMID 24185619.
- PMID 18371435.
- S2CID 5889200.
- ^ S2CID 24088675.
- S2CID 33590543.
- PMID 15494428.
- PMID 16141348.
- PMID 20945332.
- PMID 26350435.
- PMID 22250097.
- PMID 26474552.
- PMID 21242993.
- ^ "Search of: Mesenchymal stem cells - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 26 May 2023.
- PMID 23283436.
- PMID 24898458.
- PMID 19099374.
- S2CID 87157970.
- PMID 26782178.
- S2CID 28963721.
- PMID 7994030.
- S2CID 23683884.
- PMID 16146890.
- PMID 24467837.
- ^
Jiang B, Fu X, Yan L, Li S, Zhao D, Wang X, et al. (2019). "Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques". Theranostics. 9 (22): 6587–6600. PMID 31588237.
- PMID 27475781.
- S2CID 11106827.
- PMID 14086156.
- PMID 28452204.
- PMID 4455512.
- PMID 976387.
- PMID 8528172.
- PMID 29859173.
- PMID 9368181.
- PMID 30723355.
- ISSN 0362-4331. Retrieved 8 February 2021.
- ^ Office of the Commissioner (9 September 2020). "FDA Warns About Stem Cell Therapies". U.S. Food and Drug Administration.
Further reading
- Murphy MB, Moncivais K, Caplan AI (November 2013). "Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine". Experimental & Molecular Medicine. 45 (11): e54. PMID 24232253.
External links
- "Mesenchymal stem cells fact sheet". Euro Stem Cell. June 2012. Archived from the original on 27 November 2016. Retrieved 25 June 2012. scientist-reviewed and not too technical
- "Mesenchymal Stem Cell Research". Johns Hopkins University. Archived from the original on 15 October 2017. Retrieved 26 June 2012.