Mesenchymal stem cell

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


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Overview

Mesenchymal stem cells or MSCs are multipotent stem cells that can differentiate into a variety of cell types. Cell types that MSCs have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and as described lately, into beta-pancreatic islets cells. They can also transdifferentiate into neuronal cells.

While the terms Mesenchymal Stem Cell and Marrow Stromal Cell have been used interchangeably, neither term is sufficiently descriptive as discussed below:

  • Mesenchyme is embryonic connective tissue that is derived from the mesoderm which differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells.
  • Stromal cells are connective tissue cells which 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-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.

Historical background

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s.[1][2] An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues.[3][4] 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, inorganic phosphate and dexamethasone could promote their differentiation of into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers.

Modern culturing of MSCs

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 nor haematopoetic progenitors are adherent to tissue culture plastic with 24-48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct plating technique.[5]

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1.[6] STRO-1+ cells are generally more homogenous, have higher rates of adherence, and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs aren't clear.[7]

Features of MSCs

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 isn't clear if this variation is due to a different amount of "true" progenitor cells in the culture or if individuals' progenitors have variable differentiation capacities. 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. Likewise, whether this is due to a decrease in the number of MSCs, or a change to the existing MSCs isn't known. Some have reported that MSCs have an immunosuppressive effect, whereas others have found that MSCs effectively stimulate an immune response to internalized medium components such as bovine serum albumin. This confusion is directly related to the fact that as yet there is no test one could theoretically perform on a single cell to determine if that cell is an MSC or not. There are surface antigens which can be used to isolate a population of cells which have similar self-renewal and differentiation capacities, yet MSCs, as a population, typically do not all express the proposed markers, and it isn't 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 results from the interaction between the different cells which make up an MSC culture, suggesting that there is no one cell which has all the properties.

See also

References

  1. Becker AJ, McCulloch EA, Till JE (1963). "Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells". Nature. 197: 452–4. PMID 13970094.
  2. Siminovitch L, McCulloch EA, Till JE (1963). "The distribution of colony-forming cells among spleen colonies". Journal of Cellular and Comparative Physiology. 62: 327–36. PMID 14086156.
  3. Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA (1974). "Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method". Exp Hematol. 2 (2): 83–92. PMID 4455512.
  4. Friedenstein AJ, Gorskaja JF, Kulagina NN (1976). "Fibroblast precursors in normal and irradiated mouse hematopoietic organs". Exp Hematol. 4 (5): 267–74. PMID 976387.
  5. Wan C, He Q, McCaigue M, Marsh D, Li G (2006). "Nonadherent cell population of human marrow culture is a complementary source of mesenchymal stem cells (MSCs)". Journal of Orthopaedic Research. 24 (1): 21–8. PMID 16419965.
  6. Gronthos S, Graves SE, Ohta S, Simmons PJ (1994). "The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors". Blood. 84 (12): 4164–73. PMID 7994030.
  7. Oyajobi BO, Lomri A, Hott M, Marie PJ (1999). "Isolation and characterization of human clonogenic osteoblast progenitors immunoselected from fetal bone marrow stroma using STRO-1 monoclonal antibody". Journal of Bone and Mineral Research. 14 (3): 351–61. PMID 10027900.

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