Mesenchymal Stem Cells:
MSCs are multipotent precursors to many mesodermal cell lineages in vertebrate animals. They are present from early gestation through adulthood and although they have been isolated from many adult tissues. MSCs are most commonly obtained from bone marrow where they act as part of the stroma to support hematopoietic differentiation. MSCs display a stable phenotype in long-term culture and retain the potential for adipogenic, chondrogenic and osteogenic lineage differentiation in vitro and are typically involved in the healing of damaged tissues such as bone, cartilage, muscle, ligament, tendon, adipose and stroma in vivo. The utilization of MSCs has been called the “most exciting advance in cell therapy following the widespread use of HSC transplantation”. In fact, the potential of the putative functions for MSCs in regenerative medicine are such that hundreds of human trials involving MSCs are currently underway all across the globe.
Role of MSCs:
Several possible therapeutic functions exist for MSCs. First, they may directly participate in cell repopulation via expansion and differentiation. Disease caused by physical or chemical damage may soon be treated by directing the differentiation of a patient’s own stem and progenitor cells into the depleted cell types and introducing them into the affected tissue. The hypothesis that MSCs could reconstitute a population of stem cells in adipose, bone or cartilaginous tissues has been disseminated for many years and continues to be investigated today. Also, as stated previously, MSC are under investigation for direct repair of many other tissues such as heart, kidney and skin. A second possible role for MSCs is as a vessel for delivering a therapeutic transgene. Severe combined immunodeficiency (SCID) and Parkinson’s disease are examples of target diseases for stem cell-based gene therapy. The dysfunctional allele(s) that may be responsible for a disease can be circumvented by the insertion of a functional gene into the patient’s stem cells, followed by transplantation into an
appropriate tissue where they can propagate and produce the therapeutic gene product(s). Transplanted MSCs have been reported to stably reside in several tissue types including bone, cardiac and neural tissues. Also, it has been shown that human MSCs can maintain transgene expression after expansion, differentiation and transplantation into NOD/SCID mice.
Subsequent migration of transplanted MSCs toward sites of inflammation is another ability which makes transduced MSCs attractive as therapeutic agents. Due in part to their ability to migrate, MSCs have been shown to be an effective therapeutic agent to fight the tumor glioblastoma multiforme (GBM). A possibility for MSCs in tissue repair is an indirect role in support of other cell types. MSCs are known to support hematopoiesis in bone marrow by acting as part of the stroma and allogeneic MSC transplants have been shown to enhance engraftment of HSC; MSCs supply physical support and cytochemical direction by producing growth factors and cytokines, likely providing the essential cues for cell proliferation and differentiation. A more recent hypothesis suggests a similar role for those MSCs found to reside in other tissues undergoing repair and re-growth; MSCs may act as a support system for other stem and progenitor cells, instead of the direct role previously advocated.
MSCs have been shown to home to areas of hypoxia and cause rapid revascularization after injury. This ability is particularly important for treatment of ischemic injury. Ischemic tissue regeneration studies utilizing MSCs have included stroke models, skeletal muscle ischemia, and a myocardial infarction (MI) model. Heart disease is the most common cause of mortality in developed nations. Even when patients survive acute attacks like MI, however, there is often loss of functional tissue leading to decreased cardiac output and decreased quality of life. The utilization of MSCs for cardiac repair is one area of regenerative medicine where all of these cells putative therapeutic capabilities have been explored. Although studies have shown evidence of differentiation of MSCs toward cardiomyocyte-like cells for direct repopulation of the damaged area, it has recently been shown that only a very small portion of cells from MSC culture (~0.07%) retain this potential. It would be preferable to have a pure population of undifferentiated MSCs with myogenic potential for transplantation in order to take advantage of their ability to migrate to the edge of necrotic tissue and retain the potential for proliferation as the tissue begins to regenerate. This improvement is more likely due to MSCs pro-angiogenic capabilities, improving the microenvironment and secreting factors that lead to increased blood flow and greater access to nutrients required for efficient regeneration.
The fourth therapeutic role for MSCs is as an immune system modulator. Several studies have shown that allogeneic transplantation of MSCs does not appear to induce an immune response, leading to greater tolerance and reducing both the occurrence and the extent of GVHD. MSCs have been shown to alter proliferation and differentiation of B-cells, monocytes and immature dendritic cells via expression of immune modulating factors such as prostaglandin-E2 (PGE-2), IL-10 and transforming growth factor (TGF), as well as inhibiting NK cells and T-cells via indoleamine-2,3-oxygenase. Adding MSCs to a mixed lymphocyte culture suppresses T-cell proliferation, with the degree of suppression being dose-dependent and MHC independent. These findings may also be explained by the fact that MSCs do not express co-stimulatory molecules such as CD40, a protein found on APCs which must come in contact with its corresponding receptor (CD40L) on T helper cells in order for activation and subsequent proliferation of resting T cells to occur. Although the precise mechanism by which MSCs modulate T cells likely varies depending on the cell types present in vivo.