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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, beta-pancreatic islets cells^[1]. It has been shown that they can also transdifferentiate into neuronal cells in vitro ^[2]. However, in vivo results are now thought to be a misinterpretation of spontaneous cell fusion between a damaged neuron and a mesenchymal stem cell placed in the brain^{citation needed}.

Contents 1 Definition 2 History 3 Characteristics 3.1 Morphology 3.2 Detection 3.3 Differentiation capacity 3.4 Immunomodulatory effects 4 Culturing 5 Clinical use 6 See also 7 References

Definition

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 and that differentiates into 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-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.

History

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s.^[3][4] An ex 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 of transforming 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. 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 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-cell function and generate a local immunosuppresive microenvironment by secreting cytokines.^[9] 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.^[10] 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.

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.^[11]

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1.^[12] 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.^[13]

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 was a method of activating the mesenchymal stem cells then such wounds would heal much faster.

There have been recent advances in the use of autologous adult mesenchymal stem cells to regenerate human tissues, such as cartilage and meniscus in the knee^[14], partial tendon tears, and non-healing fractures.

See also

• Mesenchyme
• Multipotency
• Bone marrow

References

v • d • e Cellular differentiation: Stem cells / progenitor cell Sources/types Embryonic stem cells · Adult stem cells · Cancer stem cells Hematopoietic stem cell · Mesenchymal stem cell Cell potency Totipotent · Pluripotent · Multipotent · Oligopotent · Unipotent Related articles Stem cell treatments · Stem cell controversy · Stem cell line

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• This page was last modified on 6 October 2008, at 23:04.

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