http://en.wikipedia.org/wiki/Mesenchymal_stem_cell This page was last modified on 4 May 2010 at 00:31.

History

In 1924, Russian-born morphologist Alexander A. Maximow used extensive histological findings to identify a singular type of precursor cell within mesenchyme that develops into different types of blood cells.^[2]

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s.^[3][4] Anex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues.^[5][6] 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 into osteoblasts. In contrast, the addition oftransforming growth factor-beta (TGF-b) could induce chondrogenic markers.

Characteristics

Morphology

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 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.^[7][8]

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.

Differentiation capacity

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 as well as myocytes and possibly neuron-like cells. However, the degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical^[9]; 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. 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 allorecognition, interfere with dendritic cell and T-cellfunction, and generate a local immunosuppressive microenvironment by secreting cytokines.^[10] 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.^[11] Other studies contradict some of these findings, reflecting both the highly heterogeneous nature of MSC isolates and the considerable differences between isolates generated by the many different methods under development. ^[12]

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.^[13]

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such asSTRO-1.^[14] 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.^[15]

Clinical use

The mesenchymal stem cells can be activated and mobilized if needed. However, the efficiency is very low. For instance, damage to muscles heals very slowly. However, if there were a method of activating the mesenchymal stem cells, then such wounds would heal much faster.^{[citation needed]}

Direct injection or placement of cells into a site in need of repair may the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.^[16]Clinical case reports in orthopedic applications have been published, though the number of patients treated is small and these methods still lack rigorous study demonstrating effectiveness. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.^[17]

See also

• Mesenchyme
• Multipotency
• Bone marrow

External Links

• Mesenchymal Stem Cell News Scientific and clinical treatments emerging from Mesenchymal Stem Cell research.

References

1. ^ Anna M. Wobus (27 March 2008). Stem Cells. Springer. pp. 248–. ISBN 9783540778547. Retrieved 16 April 2010.
2. ^ Sell, Stewart (2003), Stem cell handbook, Humana Press, p. 143
3. ^ 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. doi:10.1038/197452a0. PMID 13970094.
4. ^ 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. doi:10.1002/jcp.1030620313. PMID 14086156.
5. ^ 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.
6. ^ Friedenstein AJ, Gorskaja JF, Kulagina NN (1976). "Fibroblast precursors in normal and irradiated mouse hematopoietic organs". Exp Hematol 4 (5): 267–74. PMID 976387.
7. ^ Netter, Frank H. (1987), Musculoskeletal system: anatomy, physiology, and metabolic disorders. Summit, New Jersey: Ciba-Geigy Corporation ISBN 0914168886, p.134
8. ^ 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
9. ^ Engler AJ, Sen S, Sweeny HL, Discher DE (2006). "Matrix Elasticity Directs Stem Cell Lineage Specification". Cell 126 (4): 677–689.doi:10.1016/j.cell.2006.06.044. PMID 16923388.
10. ^ Ryan JM, Barry FP, Murphy JM, Mahon BP (2005). "Mesenchymal stem cells avoid allogeneic rejection". J Inflamm (Lond) 2: 8.doi:10.1186/1476-9255-2-8. PMID 16045800.
11. ^ Ryan JM, Barry F, Murphy JM, Mahon BP (2007). "Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells". Clin. Exp. Immunol. 149 (2): 353–63. doi:10.1111/j.1365-2249.2007.03422.x (inactive 2008-06-22). PMID 17521318.
12. ^ Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells. 2007 Nov;25(11):2896-902. Epub 2007 Sep 27. Review.
13. ^ 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. doi:10.1002/jor.20023. PMID 16419965.
14. ^ 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.
15. ^ 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. doi:10.1359/jbmr.1999.14.3.351. PMID 10027900.
16. ^ Fischer, et al.. ""Pulmonary passage is a major obstacle for intravenous stem cell delivery: The pulmonary first pass effect.".
17. ^ Wakatani, et al.. ""Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells"".

Categories: Stem cells