All Things Stem Cell

Perhaps containing more different cell types than any other stem cell category, mesenchymal stem cells (MSCs) can be isolated from a wide variety of tissues in the human body. These cells have been grouped and labeled as “mesenchymal” because they are thought to have a common progenitor in the mesenchyme, an embryonic tissue (Caplan, 2005). In the developing vertebrate embryo, there are three distinct “germ layers,” or layers of cells: the endoderm, the mesoderm, and the ectoderm. Together with the germ cells, these three layers pattern out the entire body (see figure). The mesenchyme is a collection of cells mostly derived from the mesoderm that later becomes supportive structures throughout the body, including bone, cartilage, connective tissue, smooth muscle, adipose tissue, as well as the lymphatic and hematopoietic systems. Most MSCs are thought to contain progenitors in the mesenchyme (Gilbert, 2003; Conrad et al., 2009; Caplan, 2005).

The endoderm layer later becomes skin (epidermis) and the nervous system, the ectoderm becomes the digestive tract and respiratory system, and the mesoderm becomes bone, blood, muscles, connective tissue, and several organs (heart, kidney, and gonads).

However, calling MSCs “mesenchymal” can be misleading. Because this term refers to a precursor of the large MSC family, it is referring to an embryonic tissue, though the descendant MSCs can be found in both fetal and adult tissues. MSCs have been isolated from adult muscle, bone marrow, adipose tissue, cartilage, bone, potentially teeth (Caplan, 2005) as well as some fetal tissues (fetal liver, lung, amniotic fluid, and umbilical cord) (Phinney and Prockop, 2007). The MSCs isolated from any one of these tissues are multipotent and are usually shown to be MSCs by being able to differentiate into at least three different, standard mesenchymal cell types: osteocytes (bone), chondrocytes (cartilage), and adipocytes (fat) (Baksh et al., 2004). There is much evidence, though somewhat inconsistent, showing that MSCs can also differentiate into neuronal cells, which may be from mesenchyme derived from the endoderm instead of the mesoderm (Gilbert, 2003; Phinney and Prockop, 2007). Overall, MSC differentiation potentials can vary depending on what mesenchyme-derived tissue the MSCs were harvested from (Phinney and Prockop, 2007). However, MSCs cannot become hematopoietic cells (which are derived from hematopoietic stem cells), even though these cells are derived from the mesenchyme, making the label “mesenchymal” more deceptive (Gilbert, 2003; Caplan, 2005).

Though MSCs have a relatively long history, only recently have they been fully recognized as a valid stem cell family and their presence in a large array of tissue types discovered. From the 1960s to 1970s, MSCs were mainly studied from bone marrow and cartilage and mostly characterized in model organisms (Friedenstein et al., 1974; Caplan, 2005; Bianco et al., 2008). Specifically, in the 1970s Friedenstein’s group discovered that certain cells isolated from bone marrow can create clonal colonies all descendent from one original cell, and, furthermore, the colonies derived from the single cell precursor can become multiple different cell types (Friedenstein et al., 1974; Bianco et al., 2008). However, because hematopoietic stem cells were already a known stem cell population residing in bone marrow, it was many years before MSCs were widely accepted as a second stem cell population within the bone marrow. The term “mesenchymal stem cell” was later coined in 1991 by Arnold Caplan, but not widely used until 1999, though, as discussed above, its appropriateness is still in question (Bianco et al., 2008). In the 1990s progress was made using human MSCs in optimizing preservation and isolation of these cells, as well as trials in regenerative medicine. Just in the last decade, it has been found that MSCs can be isolated from skeletal muscle, adipose tissue, umbilical chords, the circulatory system, potentially dental pulp, amniotic fluids, and fetal tissues (Phinney and Prockop, 2007).

To improve future MSC applications, standardization of practices is important, and a full understanding of their potential uses in regenerative medicine is essential. Though MSCs are made up of a wide variety of cell types, most share some common proteins expressed on their cell surface that can classify them as a MSC in an assay, to some degree. However, there are no standard isolation methods for MSCs and the harvested populations, which are themselves quite heterogeneous, vary depending on the donor (Phinney and Prockop, 2007). Despite the apparent need for standardization, MSCs are becoming increasingly important in the field of regenerative medicine, having great potential for tissue repair. Specifically, MSCs have properties that inhibit inflammation and immune responses, making them ideal for this field (Phinney and Prockop, 2007). As set protocols are put into place and the large family of MSCs continues to be better understood, MSCs hold the promise of being major players in the future world of regenerative medicine.

References

Baksh, D., Song, L., Tuan, R. S. Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J. Cell. Mol. Med. 2004. 8(3): 301-16.
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Bianco, P., Robey, P. G., Simmons, P. J. Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays. Cell Stem Cell. 2008. 2(4): 313-9.
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Caplan, A. I. Review: Mesenchymal Stem Cells: Cell–Based Reconstructive Therapy in Orthopedics. Tissue Eng. 2005. 11(7-8): 1198-211.
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Conrad, C., Niess, H., Huss, R., Huber, S., von Luettichau, I., Nelson, P. J., Ott, H. C., Jauch, K., Bruns, C. J. Multipotent Mesenchymal Stem Cells Acquire a Lymphendothelial Phenotype and Enhance Lymphatic Regeneration In Vivo. Circulation. 2009. 119: 281-9.
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Friedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., Panasuk, A. F., Rudakowa, S. F., Luria, E. A., Ruadkow, I. A. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol. 1974. 2(2): 83–92.
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Gilbert, Scott F. (2003). Developmental Biology, Seventh Edition. Sunderland: Sinauer Associates Inc.

Phinney, D. G. and Prockop, D. J. Concise Review: Mesenchymal Stem/Multipotent Stromal Cells: The State of Transdifferentiation and Modes of Tissue Repair – Current Views. Stem Cells. 2007. 25:2896-902.
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Original “The Three Germ Layers” image from the Wikimedia Commons and redistributed freely as it is in the public domain.

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