An important mesenchymal stem cell (MSC) application is the differentiation of the cells into specific intra-mesenchymal and extra-mesenchymal lineages, as described below.
Directed Differentiation of Mesenchymal Stem Cells into Intra-Mesenchymal Lineages
Mesenchymal stem cells are multi-potent stem cells that can differentiate into a variety of cell lineages. Since the 1960s when scientists Ernest McCulloch and James Till revealed the clonal nature of marrow-derived mesenchymal cells, it has been understood that MSCs are characterized by plasticity and that their fate can be determined by environmental cues.
It is now evident that culturing marrow stromal cells in the presence of osteogenic stimuli, such as ascorbic acid, inorganic phosphate, and dexamethasone, can promote differentiation into osteoblasts. Alternatively, the addition of Transforming Growth Factor-beta (TGF-b) can induce chondrogenic markers. Myocyte and adipocyte differentiation can be similarly induced.
Directed differentiation of autologous mesenchymal stem cells into intra-mesenchymal lineages is an application that involves identifying pharmacological and molecular pathways that drive MSC differentiation toward mesenchymal derivatives in vitro. Its goal is to assist with predicting molecular mechanisms that will control MSC differentiation in vivo. In particular, there is a need to develop reliable methods for directing the differentiation of human mesenchymal stem cells (hMSC) within regenerative medicine applications. Most research in this area is focused on embedding mesenchymal cells into defined protein microenvironments and tracking directed differentiation through cell morphology, gene expression, and cell activity.
Directed Differentiation of MSCs into Extra-Mesenchymal Lineages
Directed differentiation of autologous mesenchymal stem cells into extra-mesenchymal lineages is another interesting area of stem cell biology, with the potential to repair tissues where resident stem cells are not accessible. The potential to differentiate MSCs into neuronal cells is a possibility that has already been demonstrated and an area that continues to be of significant clinical interest.
It has also been demonstrated that mesenchymal stem cells can differentiate into beta-pancreatic islet cells. In 2004, Chen and colleagues explored the possibility that bone marrow mesenchymal stem cells could differentiate in vitro into functional islet-like cells. His research team discovered that when rat MSCs were isolated and cultured, passaged MSCs could be induced to differentiate into typical islet-like clustered cells. Insulin mRNA and protein expressions were positive in populations of the differentiated cells, and nestin could be detected in pre-differentiated cells.
Furthermore, insulin excreted from differentiated MSCs was much higher than that from pre-differentiated cells, and injecting the differentiated MSCs into diabetic rats supported down-regulation of glucose levels in test subjects. As such, transplantation of MSC-derived islet-like functional cells may eventually be used in clinical applications for the treatment of diabetes.
However, some scientists believe that experimentation in this area is inconclusive and that substantial research needs to be done before human studies are untaken that involve mesenchymal stem cell-derived neural- or beta-pancreatic islet cells. While it is true that mechanisms for extra-mesenchymal differentiation are not well understood, cautious optimism does seem appropriate.
One reason that research in this area will continue is that there is significant medical need for extra-mesenchymal lineage cell types, including neural cells that could be used for the treatment of degenerative brain diseases, hepatic cells that could be used for diabetic therapy applications, and more. In addition, research in this area will be driven by the wide range of benefits associated with MSCs, which include ease of acquisition from a range of adult tissues, flexible methods for growth in culture, and expansion capabilities that allow for clinically relevant quantities to be obtained.
 Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 1963; 197: 452–454.
 Ye CP, et al. Culture media conditioned by heat-shocked osteoblasts enhances the osteogenesis of bone marrow-derived mesenchymal stromal cells. Cell Biochem Funct 2007; 25(3): 267-276.
 Mehlhorn AT, et al. Mesenchymal stem cells maintain TGF-beta-mediated chondrogenic phenotype in alginate bead culture. Tissue Eng 2006 Jun; 12(6): 1393-1403.
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