Mesenchymal stem cell 1600075 225064197 2008-07-11T18:37:11Z Robert M. Hunt 2049578 /* Morphology */ '''Mesenchymal stem cells''' or '''MSCs''' are [[multipotent]] [[stem cell]]s that can [[Cellular differentiation|differentiate]] into a variety of cell types. Cell types that MSCs have been shown to differentiate into [[in vitro]] or [[in vivo]] include [[osteoblast]]s, [[chondrocyte]]s, [[myocyte]]s, [[adipocyte]]s, and, as described lately, [[Beta cell|beta-pancreatic islets cells]]<ref>{{cite journal | author = Chen LB, Jiang XB, Yang L | title = Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells | journal = World journal of gastroenterology | volume = 10 (20) | pages = 3016–20 | year = 2004 | pmid = 15378785 }}</ref>. It has been suggested that they can also transdifferentiate into [[neuron|neuronal cells]], although this result is now thought to be a misinterpretation of spontaneous cell fusion between a damaged neuron and a mesenchymal stem cell placed in the brain. While the terms Mesenchymal Stem Cell and Marrow Stromal Cell have been used interchangeably, neither term is sufficiently descriptive as discussed below: * [[Mesenchyme]] is [[embryo]]nic [[connective tissue]] that is derived from the [[mesoderm]] and that differentiates into [[Haematopoiesis|hematopoietic]] and connective tissue, whereas MSCs do not differentiate into hematopoietic cells. * [[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 repair of tissue. * Because the cells, called MSCs by many labs today, can encompass multipotent cells derived from other non-[[bone marrow|marrow]] tissues, such as adult [[muscle]] side-population cells or the [[Wharton's jelly]] present in the [[umbilical cord]], as well as in the dental pulp of deciduous baby teeth, yet do not have the capacity to reconstitute an entire organ, the term '''Multipotent Stromal Cell''' has been proposed as a better replacement. ==Morphology== [[Image:Mesenchymal_Stem_Cell.jpg|center|thumb|Mesenchymal stem cell]] Mesenchymal stem cells are characterized morphologically by a small [[cell body]] with a few cell processes that are long and thin. The cell body contains a large, round [[Cell nucleus|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 fiber|reticular]] fibrils but is devoid of the other types of [[collagen]] fibrils.<ref name= "Netter">[[Frank H. Netter|Netter, Frank H.]] (1987), ''Musculoskeletal system: anatomy, physiology, and metabolic disorders''. Summit, New Jersey: Ciba-Geigy Corporation ISBN 0914168886, p.134</ref><ref name= "Brighton">Brighton, Carl T. and Robert M. Hunt (1991), "Early histologic and ultrastructural changes in medullary fracture callus", ''Journal of Bone and Joint Surgery'', '''73-A (6)''': 832-847</ref> ==History== Scientists [[Ernest McCulloch|Ernest A. McCulloch]] and [[James Till|James E. Till]] first revealed the clonal nature of marrow cells in the 1960s.<ref>{{cite journal | author = 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 | pages = 452–4 | year = 1963 | pmid = 13970094 | doi = 10.1038/197452a0 }}</ref><ref>{{cite journal | author = Siminovitch L, McCulloch EA, Till JE | title = The distribution of colony-forming cells among spleen colonies | journal = Journal of Cellular and Comparative Physiology | volume = 62| pages = 327–36 | year = 1963 | pmid = 14086156 | doi = 10.1002/jcp.1030620313 }}</ref> An ''ex vivo'' assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues.<ref>{{cite journal | author = Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA | title = Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method | journal = Exp Hematol | volume = 2| issue = 2 | pages = 83–92 | year = 1974| pmid = 4455512 }}</ref><ref>{{cite journal | author = Friedenstein AJ, Gorskaja JF, Kulagina NN | title = Fibroblast precursors in normal and irradiated mouse hematopoietic organs | journal = Exp Hematol | volume = 4 | issue = 5 | pages = 267–74 | year = 1976 | pmid = 976387 }}</ref> 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 could be determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as ''[[ascorbic acid]]'', ''[[phosphate|inorganic phosphate]]'', and ''[[dexamethasone]]'' could promote their differentiation into [[osteoblast]]s. In contrast, the addition of ''[[transforming growth factor|transforming growth factor-beta]]'' (TGF-b) could induce [[chondrocytes|chondrogenic]] markers. ==Detection== There is no test that can be performed on a single cell to determine whether that cell is an MSC. There are surface antigens that can be used to isolate a population of cells that have similar self-renewal and differentiation capacities, yet MSCs, as a population, typically do not all express the proposed markers; and it is not certain which ones must be expressed in order for that cell to be classified as an MSC. It may be that the therapeutic properties attributed to MSCs result from the interaction between the different cells that make up an MSC culture, suggesting that there is no one cell that has all the properties. ==Modern culturing== The majority of modern culture techniques still take a CFU-f approach, where raw unpurified bone marrow or ficoll-purified bone marrow [[monocytes]] are plated directly into [[cell culture]] plates or flasks. Mesenchymal stem cells, but not red blood cells or haematopoetic 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.<ref>{{cite journal | author = 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 | year = 2006 | pmid = 16419965 | doi = 10.1002/jor.20023 }}</ref> Other [[flow cytometry]]-based methods allow the sorting of bone marrow cells for specific surface markers, such as [[STRO-1]].<ref>{{cite journal | author = 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 | year = 1994 | pmid = 7994030 }}</ref> 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.<ref>{{cite journal | author = 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 | year = 1999 | pmid = 10027900 | doi = 10.1359/jbmr.1999.14.3.351 }}</ref> == Differentiation-ability == MSCs have a large capacity for self-renewal while maintaining their multipotency. Beyond that, there is little that can be definitively said. The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes, and chondrocytes. However, the degree to which the culture will differentiate varies among individuals; 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 [[proliferation|proliferate]] and [[differentiation|differentiate]] is known to decrease with the age of the donor, as well as the time in culture. Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known. ==Immunomodulatory effects== Numerous studies have demonstrated that human MSC avoid [[Transplant rejection|allorecognition]], interfere with [[dendritic cell]] and [[T-cell]] function and generate a local immunosuppresive microenvironment by secreting [[cytokine]]s.<ref>{{cite journal |author=Ryan JM, Barry FP, Murphy JM, Mahon BP |title=Mesenchymal stem cells avoid allogeneic rejection |journal=J Inflamm (Lond) |volume=2 |issue= |pages=8 |year=2005 |pmid=16045800 |doi=10.1186/1476-9255-2-8 }}</ref> It has also been shown that the immunomodulatory function of human MSC is enhanced when the cells are exposed to an inflammatory environment characterised by the presence of elevated local [[interferon-gamma]] levels.<ref name="pmid17521318">{{cite journal |author=Ryan JM, Barry F, Murphy JM, Mahon BP |title=Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells |journal=Clin. Exp. Immunol. |volume=149 |issue=2 |pages=353–63 |year=2007 |pmid=17521318 |doi=10.1111/j.1365-2249.2007.03422.x |doi_brokendate=2008-06-22 }}</ref> Other studies contradict some of these findings, reflecting both the highly heterogenous nature of MSC isolates and the considerable differences between isolates generated by the many different methods under development. == Clinical use == The mesenchymal stem cells can be activated and [[cell mobility|mobilized]] if needed. However, the efficiency is very low. For instance, damage to muscles heals very slowly. However, if there was a method of activating the mesenchymal stem cells then such wounds would heal much faster. Therefore, there is currently a lot of research occuring on MSCs. ==See also== * [[Mesenchyme]] * [[Multipotency]] * [[Bone marrow]] ==References== <references/> [[Category:Stem cells]] [[ar:خلية جذعية متعلقة باللحمة المتوسطة]] [[ja:間葉系幹細胞]]