mesenchymal stem cell

Mesenchymal stem cells (MSCs), a term first used (in 1991) by Arnold Caplan at Case Western Reserve University,{{cite journal |vauthors=Bianco P, Robey PG, Simmons PJ |date=April 2008 |title=Mesenchymal stem cells: revisiting history, concepts, and assays |journal=Cell Stem Cell |volume=2 |issue=4 |pages=313–319 |doi=10.1016/j.stem.2008.03.002 |pmc=2613570 |pmid=18397751}} are characterized morphologically by a small cell body with long, thin cell processes. While the terms mesenchymal stem cell (MSC) and marrow stromal cell have been used interchangeably for many years, neither term is sufficiently descriptive:

• 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.{{cite journal | vauthors = Porcellini A | title = Regenerative medicine: a review | journal = Revista Brasileira de Hematologia e Hemoterapia | year = 2009 | volume = 31 | issue = Suppl. 2 | doi = 10.1590/S1516-84842009000800017 | doi-access = free }}
• 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.{{cite journal | vauthors = Valero MC, Huntsman HD, Liu J, Zou K, Boppart MD | title = Eccentric exercise facilitates mesenchymal stem cell appearance in skeletal muscle | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e29760 | year = 2012 | pmid = 22253772 | pmc = 3256189 | doi = 10.1371/journal.pone.0029760 | bibcode = 2012PLoSO...729760V | doi-access = free }}
• The term encompasses multipotent cells derived from other non-marrow tissues, such as placenta,{{cite journal | vauthors = Wang S, Qu X, Zhao RC | title = Clinical applications of mesenchymal stem cells | journal = Journal of Hematology & Oncology | volume = 5 | pages = 19 | date = April 2012 | pmid = 22546280 | pmc = 3416655 | doi = 10.1186/1756-8722-5-19 | doi-access = free }} umbilical cord blood, adipose tissue, adult muscle, corneal stroma,{{cite journal | vauthors = Branch MJ, Hashmani K, Dhillon P, Jones DR, Dua HS, Hopkinson A | title = Mesenchymal stem cells in the human corneal limbal stroma | journal = Investigative Ophthalmology & Visual Science | volume = 53 | issue = 9 | pages = 5109–16 | date = August 2012 | pmid = 22736610 | doi = 10.1167/iovs.11-8673 | doi-access =}} or the dental pulp of deciduous (baby) teeth.{{cite journal |vauthors=Liu J, Yu F, Sun Y, Jiang B, Zhang W, Yang J, Xu G, Liang A, Liu S |date=March 2015 |title=Concise Reviews: Characteristics and Potential Applications of Human Dental Tissue-Derived Mesenchymal Stem Cells |journal=Stem Cells |volume=33 |issue=3 |pages=627–38 |doi=10.1002/stem.1909 |pmid=25447379 | doi-access = free}} The cells do not have the capacity to reconstitute an entire organ.
• Evidence shows that MSCs originate from progenitor perivascular cells called pericytes that reside on vessels.{{cite journal |vauthors=Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Péault B |title=A perivascular origin for mesenchymal stem cells in multiple human organs |journal=Cell Stem Cell |volume=3 |issue=3 |pages=301–13 |date=September 2008 |pmid=18786417 |doi=10.1016/j.stem.2008.07.003 |url=https://pubmed.ncbi.nlm.nih.gov/18786417/}}

File:Human bone marrow derived MSCs.jpg

File:Human mesenchymal stem cells.gif microscope]]

The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria, and polyribosomes. The cells, which are long and thin, are widely dispersed, and the adjacent extracellular matrix is populated by a few reticular fibrils, but is devoid of the other types of collagen fibrils.{{cite book | vauthors = Netter FH |author-link=Frank H. Netter |year=1987 |title=Musculoskeletal system: anatomy, physiology, and metabolic disorders |location=Summit, New Jersey |publisher=Ciba-Geigy Corporation |isbn=978-0-914168-88-1 |page=134}}{{cite journal | vauthors = Brighton CT, Hunt RM | title = Early histological and ultrastructural changes in medullary fracture callus | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 73 | issue = 6 | pages = 832–847 | date = July 1991 | pmid = 2071617 | doi = 10.2106/00004623-199173060-00006 }} These distinctive morphological features of mesenchymal stem cells can be visualized label-free using live cell imaging.{{citation needed|date=February 2025}}

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.{{cite journal |vauthors=Hematti P |date=May 2012 |title=Mesenchymal stromal cells and fibroblasts: a case of mistaken identity? |journal=Cytotherapy |volume=14 |issue=5 |pages=516–21 |doi=10.3109/14653249.2012.677822 |pmid=22458957}}

Cultured MSCs also express on their surface CD73, CD90 and CD105, while lacking the expression of CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR surface markers.

A study in Science, "Multilineage Potential of Adult Mesenchymal Stem Cells," describes how MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex vivo. As of January 2025, this paper has been cited over 30,000 times.{{cite journal |display-authors=6 |vauthors=Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E |date=1 January 2006 |title=Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement |journal=Cytotherapy |volume=8 |issue=4 |pages=315–7 |doi=10.1080/14653240600855905 |pmid=16923606}}

MSCs are found throughout the human body.

Bone marrow was the original source of MSCs,{{cite journal |vauthors=Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J |date=September 2012 |title=Same or Not the Same? Comparison of Adipose Tissue-Derived Versus Bone Marrow-Derived Mesenchymal Stem and Stromal Cells|journal=Stem Cells and Development |volume=21 |issue=14 |pages=2724–52 |doi=10.1089/scd.2011.0722 |pmid=22468918}} 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.{{cite journal | vauthors = Gregory CA, Prockop DJ, Spees JL | title = Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation | journal = Experimental Cell Research | volume = 306 | issue = 2 | pages = 330–5 | date = June 2005 | pmid = 15925588 | doi = 10.1016/j.yexcr.2005.03.018 | series = Molecular Control of Stem Cell Differentiation }}

Mesenchymal cells from menstrual blood ([https://pt.wikipedia.org/wiki/C%C3%A9lulas_Mesenquimais_do_Sangue_Menstrual_(CeSaM)#cite_note-1 CeSaM]) are easy to obtain, do not require invasive procedures like other mesenchymal cell sources, and the material is abundant. Menstrual blood can be collected on the days of greatest flow during menstruation, stored in a urine collector and can be taken to the laboratory to be processed immediately or remain under refrigeration until processing. The cells expand rapidly and have an excellent survival rate in the laboratory. All these characteristics make CeSaM an interesting source of cells doi:10.3389/fgene.2022.957164

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.{{cite journal |vauthors=Liau LL, Ruszymah BH, Ng MH, Law JX |date=Jan 2020 |title=Characteristics and Clinical Applications of Wharton's Jelly-Derived Mesenchymal Stromal Cells |journal=Current Research in Translational Medicine |volume=68 |issue=1 |pages=5–16 |doi=10.1016/j.retram.2019.09.001 |pmid=31543433 |s2cid=202731274 |doi-access= }}

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.{{cite journal | vauthors = Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C | title = Adipose-derived stem cells: isolation, expansion and differentiation | journal = Methods | volume = 45 | issue = 2 | pages = 115–20 | date = June 2008 | pmid = 18593609 | pmc = 3668445 | doi = 10.1016/j.ymeth.2008.03.006 | series = Methods in stem cell research }}

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 chondrocytes, cardiomyocytes, melanocytes, and hepatocyte‐like cells in vitro.

Stem cells are present in amniotic fluid. As many as 1 in 100 cells collected during amniocentesis are pluripotent mesenchymal stem cells.{{cite web|title=What is Cord Tissue?|url=http://cordadvantage.com/cord-tissue-banking.html|publisher=CordAdvantage.com|date=2018-10-30}}

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 MSCs.{{cite journal | vauthors = Sen B, Paradise CR, Xie Z, Sankaran J, Uzer G, Styner M, Meyer M, Dudakovic A, van Wijnen AJ, Rubin J | display-authors = 6 | title = β-Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2 | journal = Journal of Bone and Mineral Research | volume = 35 | issue = 6 | pages = 1149–1162 | date = June 2020 | pmid = 32022326 | pmc = 7295671 | doi = 10.1002/jbmr.3975 | doi-access = free }} The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes and chondrocytes as well as myocytes.{{citation needed|date=February 2025}}

Doubt remains about whether the MSC-derived neurons are functional.{{cite journal | vauthors = Franco Lambert AP, Fraga Zandonai A, Bonatto D, Cantarelli Machado D, Pêgas Henriques JA | title = Differentiation of human adipose-derived adult stem cells into neuronal tissue: does it work? | journal = Differentiation; Research in Biological Diversity | volume = 77 | issue = 3 | pages = 221–8 | date = March 2009 | pmid = 19272520 | doi = 10.1016/j.diff.2008.10.016 }} The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical;{{cite journal | vauthors = Engler AJ, Sen S, Sweeney HL, Discher DE | title = Matrix elasticity directs stem cell lineage specification | journal = Cell | volume = 126 | issue = 4 | pages = 677–89 | date = August 2006 | pmid = 16923388 | doi = 10.1016/j.cell.2006.06.044 | s2cid = 16109483 | doi-access = free }} 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.{{cite journal | vauthors = Choudhery MS, Badowski M, Muise A, Pierce J, Harris DT | title = Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation | journal = Journal of Translational Medicine | volume = 12 | issue = 1 | pages = 8 | date = January 2014 | pmid = 24397850 | pmc = 3895760 | doi = 10.1186/1479-5876-12-8 | doi-access = free }} 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|date=March 2011}}

MSCs have an effect on innate and specific immune cells, and research has shown an ability to suppress tumor growth.{{cite journal | vauthors =Banerjee K, Chattopadhyay A, Banerjee S |date= July 2022 |title=Understanding the association of stem cells in fetal development and carcinogenesis during pregnancy |journal=Advances in Cancer Biology - Metastasis |language=en |volume=4 |pages=100042 |doi=10.1016/j.adcanc.2022.100042 |s2cid=248485831 |issn=2667-3940|doi-access=free }} MSCs produce many immunomodulatory molecules including prostaglandin E2 (PGE2),{{cite journal | vauthors = Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L | title = MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2 | journal = Blood | volume = 113 | issue = 26 | pages = 6576–6583 | date = June 2009 | pmid = 19398717 | doi = 10.1182/blood-2009-02-203943 | s2cid = 206878089 | doi-access = free }} nitric oxide,{{cite journal | vauthors = Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S, Shao C, Shi Y | display-authors = 6 | title = Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression | journal = Journal of Immunology | volume = 184 | issue = 5 | pages = 2321–2328 | date = March 2010 | pmid = 20130212 | pmc = 2881946 | doi = 10.4049/jimmunol.0902023 }} indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL-6), and other surface markers such as FasL,{{cite journal | vauthors = Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, Cai T, Chen W, Sun L, Shi S | display-authors = 6 | title = Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis | journal = Cell Stem Cell | volume = 10 | issue = 5 | pages = 544–555 | date = May 2012 | pmid = 22542159 | pmc = 3348385 | doi = 10.1016/j.stem.2012.03.007 }} PD-L1 and PD-L2.{{cite journal | vauthors = Davies LC, Heldring N, Kadri N, Le Blanc K | title = Mesenchymal Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression | journal = Stem Cells | volume = 35 | issue = 3 | pages = 766–776 | date = March 2017 | pmid = 27671847 | pmc = 5599995 | doi = 10.1002/stem.2509 }}

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.{{cite journal | vauthors = Kim J, Hematti P | title = Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages | journal = Experimental Hematology | volume = 37 | issue = 12 | pages = 1445–53 | date = December 2009 | pmid = 19772890 | pmc = 2783735 | doi = 10.1016/j.exphem.2009.09.004 }} Further, PGE2 inhibits the ability of mast cells to degranulate and produce TNF-α.{{cite journal | vauthors = Brown JM, Nemeth K, Kushnir-Sukhov NM, Metcalfe DD, Mezey E | title = Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism | journal = Clinical and Experimental Allergy | volume = 41 | issue = 4 | pages = 526–34 | date = April 2011 | pmid = 21255158 | pmc = 3078050 | doi = 10.1111/j.1365-2222.2010.03685.x }}{{cite journal | vauthors = Kay LJ, Yeo WW, Peachell PT | title = Prostaglandin E2 activates EP2 receptors to inhibit human lung mast cell degranulation | journal = British Journal of Pharmacology | volume = 147 | issue = 7 | pages = 707–13 | date = April 2006 | pmid = 16432506 | pmc = 1751511 | doi = 10.1038/sj.bjp.0706664 }} 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.{{cite journal | vauthors = Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L | title = Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation | journal = Blood | volume = 107 | issue = 4 | pages = 1484–90 | date = February 2006 | pmid = 16239427 | doi = 10.1182/blood-2005-07-2775 | hdl = 11567/267587 | hdl-access = free }} MSCs inhibit respiratory flare and apoptosis of neutrophils by production of cytokines IL-6 and IL-8.{{cite journal | vauthors = Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F, Ottonello L, Pistoia V | display-authors = 6 | title = Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche | journal = Stem Cells | volume = 26 | issue = 1 | pages = 151–62 | date = January 2008 | pmid = 17932421 | doi = 10.1634/stemcells.2007-0416 | s2cid = 32230553 | doi-access = free }} Differentiation and expression of dendritic cell surface markers is inhibited by IL-6 and PGE2 of MSCs.{{cite journal | vauthors = Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N | title = Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells | journal = Blood | volume = 105 | issue = 10 | pages = 4120–6 | date = May 2005 | pmid = 15692068 | doi = 10.1182/blood-2004-02-0586 | doi-access = free }} 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.{{cite journal | vauthors = Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y | title = Immunobiology of mesenchymal stem cells | journal = Cell Death and Differentiation | volume = 21 | issue = 2 | pages = 216–25 | date = February 2014 | pmid = 24185619 | pmc = 3890955 | doi = 10.1038/cdd.2013.158 }}

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. These include nitric oxide,{{cite journal | vauthors = Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y | display-authors = 6 | title = Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide | journal = Cell Stem Cell | volume = 2 | issue = 2 | pages = 141–50 | date = February 2008 | pmid = 18371435 | doi = 10.1016/j.stem.2007.11.014 | doi-access = free }} PGE2, HGF,{{cite journal | vauthors = Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM | display-authors = 6 | title = Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli | journal = Blood | volume = 99 | issue = 10 | pages = 3838–43 | date = May 2002 | pmid = 11986244 | doi = 10.1182/blood.v99.10.3838 | s2cid = 5889200 | doi-access = free | hdl = 11379/598065 | hdl-access = free }} and activation of receptor PD-1.{{cite journal | vauthors = Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G | title = Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway | journal = European Journal of Immunology | volume = 35 | issue = 5 | pages = 1482–90 | date = May 2005 | pmid = 15827960 | doi = 10.1002/eji.200425405 | s2cid = 24088675 | doi-access = free }} MSCs reduce T cell proliferation between G0 and G1 cell cycle phases{{cite journal | vauthors = Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F | title = Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells | journal = Blood | volume = 105 | issue = 7 | pages = 2821–7 | date = April 2005 | pmid = 15591115 | doi = 10.1182/blood-2004-09-3696 | s2cid = 33590543 | doi-access = free }} and decrease the expression of IFNγ of Th1 cells while increasing the expression of IL-4 of Th2 cells.{{cite journal | vauthors = Aggarwal S, Pittenger MF | title = Human mesenchymal stem cells modulate allogeneic immune cell responses | journal = Blood | volume = 105 | issue = 4 | pages = 1815–22 | date = February 2005 | pmid = 15494428 | doi = 10.1182/blood-2004-04-1559 | doi-access = free }} MSCs also inhibit the proliferation of B-lymphocytes between G0 and G1 cell cycle phases.{{cite journal | vauthors = Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A | display-authors = 6 | title = Human mesenchymal stem cells modulate B-cell functions | journal = Blood | volume = 107 | issue = 1 | pages = 367–72 | date = January 2006 | pmid = 16141348 | doi = 10.1182/blood-2005-07-2657 | doi-access = free }}

MSCs produce several antimicrobial peptides (AMPs), including human cathelicidin LL-37,{{cite journal | vauthors = Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW, Matthay MA | title = Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37 | journal = Stem Cells | volume = 28 | issue = 12 | pages = 2229–38 | date = December 2010 | pmid = 20945332 | pmc = 3293245 | doi = 10.1002/stem.544 }} β-defensins,{{cite journal | vauthors = Sung DK, Chang YS, Sung SI, Yoo HS, Ahn SY, Park WS | title = Antibacterial effect of mesenchymal stem cells against Escherichia coli is mediated by secretion of beta- defensin- 2 via toll- like receptor 4 signalling | journal = Cellular Microbiology | volume = 18 | issue = 3 | pages = 424–36 | date = March 2016 | pmid = 26350435 | pmc = 5057339 | doi = 10.1111/cmi.12522 }} lipocalin 2{{cite journal | vauthors = Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, Matthay MA | title = Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia | journal = Thorax | volume = 67 | issue = 6 | pages = 533–9 | date = June 2012 | pmid = 22250097 | pmc = 3358432 | doi = 10.1136/thoraxjnl-2011-201176 }} and hepcidin.{{cite journal | vauthors = Alcayaga-Miranda F, Cuenca J, Martin A, Contreras L, Figueroa FE, Khoury M | title = Combination therapy of menstrual derived mesenchymal stem cells and antibiotics ameliorates survival in sepsis | journal = Stem Cell Research & Therapy | volume = 6 | pages = 199 | date = October 2015 | pmid = 26474552 | pmc = 4609164 | doi = 10.1186/s13287-015-0192-0 | doi-access = free }} These peptides, together with the enzyme indoleamine 2,3-dioxygenase (IDO), are responsible for the broad-spectrum antibacterial activity of MSCs.{{cite journal | vauthors = Meisel R, Brockers S, Heseler K, Degistirici O, Bülle H, Woite C, Stuhlsatz S, Schwippert W, Jäger M, Sorg R, Henschler R, Seissler J, Dilloo D, Däubener W | display-authors = 6 | title = Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase | journal = Leukemia | volume = 25 | issue = 4 | pages = 648–54 | date = April 2011 | pmid = 21242993 | doi = 10.1038/leu.2010.310 | doi-access = free }}

File:Typical gross appearance of a tubular cartilaginous construct engineered from amniotic mesenchymal stem cells..jpg

{{See also|Clinical uses of mesenchymal stem cells}}

Mesenchymal stem cells can be activated and mobilized in reaction to injury and infection. As of May 2024, a search for "mesenchymal stem cells" or "mesenchymal stromal cells" at ClinicalTrials.gov returns more than 1,760 studies featuring MSCs{{cite web |title=Search of: Mesenchymal stem cells - List Results - ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/results?cond=&term=Mesenchymal+stem+cells&cntry=&state=&city=&dist= |access-date=2023-05-26 |website=clinicaltrials.gov |language=en}} for more than 920 conditions.

Clinical studies investigating the efficacy of mesenchymal stem cells in treating diseases are in clinical development around the world, particularly treating autoimmune diseases, graft versus host disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus and systemic sclerosis.{{cite journal | vauthors = Figueroa FE, Carrión F, Villanueva S, Khoury M | title = Mesenchymal stem cell treatment for autoimmune diseases: a critical review | journal = Biological Research | volume = 45 | issue = 3 | pages = 269–77 | year = 2012 | pmid = 23283436 | doi = 10.4067/S0716-97602012000300008 | doi-access = free }}{{cite journal | vauthors = Sharma RR, Pollock K, Hubel A, McKenna D | title = Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices | journal = Transfusion | volume = 54 | issue = 5 | pages = 1418–37 | date = May 2014 | pmid = 24898458 | pmc = 6364749 | doi = 10.1111/trf.12421 }}

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.{{cite journal | vauthors = Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS | display-authors = 6 | title = Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect | journal = Stem Cells and Development | volume = 18 | issue = 5 | pages = 683–92 | date = June 2009 | pmid = 19099374 | pmc = 3190292 | doi = 10.1089/scd.2008.0253 }}

Further studies into the mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair.{{cite journal |vauthors=Heirani-Tabasi A, Hassanzadeh M, Hemmati-Sadeghi S, Shahriyari M, Raeesolmohaddeseen M |year=2015 |title=Mesenchymal Stem Cells; Defining the Future of Regenerative Medicine |journal=Journal of Genes and Cells |volume=1 |issue=2 |pages=34–39 |doi=10.15562/gnc.15 |s2cid=87157970}}{{cite journal |display-authors=6 |vauthors=Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, Hoon M, Bauer G, Fink KD, Fury B, Hendrix KJ, Chedin F, El-Andaloussi S, Hwang B, Mulligan MS, Lehtiö J, Nolta JA |date=March 2016 |title=Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling |journal=Stem Cells |volume=34 |issue=3 |pages=601–13 |doi=10.1002/stem.2298 |pmc=5785927 |pmid=26782178}}

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 mononuclear cells are plated directly into cell culture plates or flasks. Mesenchymal stem cells, but not red blood cells or hematopoietic progenitors, are adherent to tissue culture plastic within 24 to 48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct-plating technique.{{cite journal | vauthors = Wan C, He Q, McCaigue M, Marsh D, Li G | title = Nonadherent cell population of human marrow culture is a complementary source of mesenchymal stem cells (MSCs) | journal = Journal of Orthopaedic Research | volume = 24 | issue = 1 | pages = 21–8 | date = January 2006 | pmid = 16419965 | doi = 10.1002/jor.20023 | s2cid = 28963721 | doi-access =}}

Researchers have successfully isolated and expanded MSCs from marrow samples, demonstrating their ability to differentiate into specific cell lineages under controlled laboratory conditions. Environmental factors like nutrients, spatial organization, and signaling molecules influence MSC behavior and differentiation.{{cite journal | last1=Pittenger | first1=Mark F. | last2=Mackay | first2=Alastair M. | last3=Beck | first3=Stephen C. | last4=Jaiswal | first4=Rama K. | last5=Douglas | first5=Robin | last6=Mosca | first6=Joseph D. | last7=Moorman | first7=Mark A. | last8=Simonetti | first8=Donald W. | last9=Craig | first9=Stewart | last10=Marshak | first10=Daniel R. | title=Multilineage Potential of Adult Human Mesenchymal Stem Cells | journal=Science | volume=284 | issue=5411 | date=1999-04-02 | issn=0036-8075 | doi=10.1126/science.284.5411.143 | pages=143–147| pmid=10102814 | bibcode=1999Sci...284..143P }}

Researchers developed a special nanoparticle system to help MSCs support bone regeneration more effectively by delivering a protective gene (Nrf2) and a steroid (dexamethasone). This method helped repair DNA damage quickly, reduced harmful molecules, and improved bone healing in rats.{{cite journal | last1=Park | first1=Ji Sun | last2=Jeon | first2=Hayoung | last3=Lee | first3=Yeeun | last4=Cheon | first4=Seo Young | last5=Lee | first5=Donghyun | last6=Lim | first6=Seong Gi | last7=Koo | first7=Heebeom | title=Rapid DNA Repair in Mesenchymal Stem Cells and Bone Regeneration by Nanoparticle-Based Codelivery of Nrf2-mRNA and Dexamethasone | journal=ACS Nano | volume=18 | issue=46 | date=2024-11-19 | issn=1936-0851 | doi=10.1021/acsnano.4c08939 | pages=31877–31890| pmid=39520360 }}

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1.{{cite journal | vauthors = Gronthos S, Graves SE, Ohta S, Simmons PJ | title = The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors | journal = Blood | volume = 84 | issue = 12 | pages = 4164–73 | date = December 1994 | pmid = 7994030 | doi = 10.1182/blood.V84.12.4164.bloodjournal84124164 | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=7994030 | doi-access = free }} 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.{{cite journal | vauthors = Oyajobi BO, Lomri A, Hott M, Marie PJ | title = Isolation and characterization of human clonogenic osteoblast progenitors immunoselected from fetal bone marrow stroma using STRO-1 monoclonal antibody | journal = Journal of Bone and Mineral Research | volume = 14 | issue = 3 | pages = 351–61 | date = March 1999 | pmid = 10027900 | doi = 10.1359/jbmr.1999.14.3.351 | s2cid = 23683884 | doi-access = free }}

Methods of immunodepletion using such techniques as MACS have also been used in the negative selection of MSCs.{{cite journal | vauthors = Tondreau T, Lagneaux L, Dejeneffe M, Delforge A, Massy M, Mortier C, Bron D | title = Isolation of BM mesenchymal stem cells by plastic adhesion or negative selection: phenotype, proliferation kinetics and differentiation potential | journal = Cytotherapy | volume = 6 | issue = 4 | pages = 372–9 | date = 1 January 2004 | pmid = 16146890 | doi = 10.1080/14653240410004943 }}

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.{{cite journal | vauthors = Iudicone P, Fioravanti D, Bonanno G, Miceli M, Lavorino C, Totta P, Frati L, Nuti M, Pierelli L | display-authors = 6 | title = Pathogen-free, plasma-poor platelet lysate and expansion of human mesenchymal stem cells | journal = Journal of Translational Medicine | volume = 12 | pages = 28 | date = January 2014 | pmid = 24467837 | pmc = 3918216 | doi = 10.1186/1479-5876-12-28 | doi-access = free }}

New research titled Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques

{{cite journal | vauthors = Jiang B, Fu X, Yan L, Li S, Zhao D, Wang X, Duan Y, Yan Y, Li E, Wu K, Inglis BM, Ji W, Xu RH, Si W | display-authors = 6 | title = Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques | journal = Theranostics | volume = 9 | issue = 22 | pages = 6587–6600 | year = 2019 | pmid = 31588237 | pmc = 6771254 | doi = 10.7150/thno.35391 }} Various chemicals and methods, including low-level laser irradiation, have been used to increase stem cell proliferation.{{cite journal | vauthors = Borzabadi-Farahani A | title = Effect of low-level laser irradiation on proliferation of human dental mesenchymal stem cells; a systemic review | journal = Journal of Photochemistry and Photobiology. B, Biology | volume = 162 | pages = 577–582 | date = September 2016 | pmid = 27475781 | doi = 10.1016/j.jphotobiol.2016.07.022 | bibcode = 2016JPPB..162..577B }}

MSC exosomes are being explored as a potential treatment for disseminated intravascular coagulation (DIC) due to their anti-inflammatory and anticoagulant properties. A 2024 research suggests that MSC-Exos may help regulate immune responses, reduce pro-inflammatory signaling, and restore balance in the coagulation-fibrinolysis system.{{cite journal | last1=Wang | first1=Chengran | last2=Zhao | first2=Xiaoqing | last3=Wang | first3=Keyan | last4=Liang | first4=Huixin | last5=Chen | first5=Shuhan | last6=Liu | first6=Yajie | last7=Yao | first7=Hua | last8=Jiang | first8=Jinlan | title=Prospective Application of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Disseminated Intravascular Coagulation | journal=International Journal of Nanomedicine | publisher=Informa UK Limited | volume=19 | year=2024 | issn=1178-2013 | doi=10.2147/ijn.s467158 | doi-access=free | pages=11957–11971}}

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s.{{cite journal | vauthors = Becker AJ, McCulloch EA, Till JE | title = Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells | journal = Nature | volume = 197 | issue = 4866 | pages = 452–4 | date = February 1963 | pmid = 13970094 | doi = 10.1038/197452a0 | bibcode = 1963Natur.197..452B | hdl = 1807/2779 | s2cid = 11106827 | hdl-access = free }}{{cite journal | vauthors = Siminovitch L, Mcculloch EA, Till JE | journal = Journal of Cellular and Comparative Physiology | volume = 62 | issue = 3 | pages = 327–36 | date = December 1963 | pmid = 14086156 | doi = 10.1002/jcp.1030620313 | hdl = 1807/2778 | title = The distribution of colony-forming cells among spleen colonies | hdl-access = free }} In 1970, Arnold Caplan identified certain conditions by which mesodermal cells differentiate into cartilage or myogenic (muscle) tissue and bone and named them mesenchymal stem cells.

An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues.{{cite journal | vauthors = Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luriá EA, Ruadkow IA | title = Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method | journal = Experimental Hematology | volume = 2 | issue = 2 | pages = 83–92 | year = 1974 | pmid = 4455512 }}{{cite journal | vauthors = Friedenstein AJ, Gorskaja JF, Kulagina NN | title = Fibroblast precursors in normal and irradiated mouse hematopoietic organs | journal = Experimental Hematology | volume = 4 | issue = 5 | pages = 267–74 | date = September 1976 | pmid = 976387 }} In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f).{{citation needed|date=February 2025}}

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 ascorbic acid, inorganic phosphate and dexamethasone could promote their differentiation into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers.{{Citation needed|date=March 2011}}

The first clinical trials of MSCs were completed by Osiris Therapeutics, a pharmaceutical company co-founded in 1995 by Caplan, with entrepreneur Kevin Kimberlin and others,{{cite web | title=New CEO at Osiris toiling as clock ticks | last=Bell | first=Julie | work=The Baltimore Sun | page=C1 | via=Newspapers.com | date=September 26, 2002 | url=https://www.newspapers.com/article/the-baltimore-sun-new-osiris-ceo-part-1/107612420/ | access-date=2025-01-30}} when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment.{{cite journal | vauthors = Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI | title = Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use | journal = Bone Marrow Transplantation | volume = 16 | issue = 4 | pages = 557–564 | date = October 1995 | pmid = 8528172 | doi =}} 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.{{cite journal | vauthors = Galipeau J, Sensébé L | title = Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities | journal = Cell Stem Cell | volume = 22 | issue = 6 | pages = 824–833 | date = June 2018 | doi = 10.1016/j.stem.2018.05.004 | pmid = 29859173 | pmc = 6434696 }}

Since then, more than 1,500 clinical trials have been conducted to treat numerous conditions.{{cite journal | vauthors = Lazarus HM, Haynesworth SE, Gerson SL, Caplan AI | title = Human bone marrow-derived mesenchymal (stromal) progenitor cells (MPCs) cannot be recovered from peripheral blood progenitor cell collections | journal = Journal of Hematotherapy | volume = 6 | issue = 5 | pages = 447–455 | date = October 1997 | pmid = 9368181 | doi = 10.1089/scd.1.1997.6.447 }}

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."{{cite journal | vauthors = Caplan AI | title = Medicinal signalling cells: they work, so use them | journal = Nature | volume = 566 | issue = 7742 | pages = 39 | date = February 2019 | pmid = 30723355 | doi = 10.1038/d41586-019-00490-6 | doi-access = free | bibcode = 2019Natur.566R..39C }} 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.{{citation needed|date=February 2025}}

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.{{cite news| vauthors = Vigdor N |date=2021-02-04|title=Lawmaker Promoted Stem Cell Therapy for Covid-19 in Fraud Scheme, U.S. Says|language=en-US|work=The New York Times|url=https://www.nytimes.com/2021/02/03/us/Tricia-Derges-fake-stem-cell-cure-covid.html|access-date=2021-02-08|issn=0362-4331}}{{cite web| author = Office of the Commissioner |date=2020-09-09 |title=FDA Warns About Stem Cell Therapies |url= https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies |archive-url= https://web.archive.org/web/20190428194333/https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies |url-status= dead |archive-date= 28 April 2019 | work = U.S. Food and Drug Administration |language=en }}

• Bone marrow
• Fibroblast
• Muse cell
• Intramembranous ossification
• Mesenchyme
• Multipotency
• Cord lining
• Bone marrow adipose tissue
• List of human cell types derived from the germ layers

{{Reflist}}

• {{cite journal | vauthors = Murphy MB, Moncivais K, Caplan AI | title = Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine | journal = Experimental & Molecular Medicine | volume = 45 | issue = 11 | pages = e54 | date = November 2013 | pmid = 24232253 | pmc = 3849579 | doi = 10.1038/emm.2013.94 }}

• {{cite web | url = http://www.eurostemcell.org/factsheet/mesenchymal-stem-cells-other-bone-marrow-stem-cells | title = Mesenchymal stem cells fact sheet | date = June 2012 | work = Euro Stem Cell | access-date = 25 June 2012 | archive-url = https://web.archive.org/web/20161127202424/http://www.eurostemcell.org/factsheet/mesenchymal-stem-cells-other-bone-marrow-stem-cells | archive-date = 27 November 2016 | url-status = dead }} scientist-reviewed and not too technical
• {{cite web | url = http://www.hopkinsmedicine.org/stem_cell_research/cell_identity | title = Mesenchymal Stem Cell Research | work = Johns Hopkins University | access-date = 26 June 2012 | archive-url = https://web.archive.org/web/20171015071218/http://www.hopkinsmedicine.org/stem_cell_research/cell_identity/ | archive-date = 15 October 2017 | url-status = dead }}

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Category:Stem cells