Mesenchymal stem cells (MSCs), adherent fibroblastoid cells, present in bone marrow and many other tissues can be easily isolated and expanded in vitro. They are capable of differentiating into different cell types such as osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial cells and neuronal cells. Such immense plasticity coupled with their ability to modulate the activity of immune cells makes them attractive for stem cell-based therapy aimed at treating previously incurable disorders. Preclinical studies have reported successful use of MSCs for delivering therapeutic proteins and repairing defects in a variety of disease models. These studies highlighted the in vivo potential of MSCs and their ability to home to injury sites and modify the microenvironment by secreting paracrine factors to augment tissue repair. Their therapeutic applicability has been widened by genetic modification to enhance differentiation and tissue targeting, and use in tissue engineering. Clinical trials for diseases such as osteogenesis imperfecta, graft-versus-host disease and myocardial infarction have shown some promise, demonstrating the safe use of both allogeneic and autologous cells. However, lack of knowledge of MSC behaviour and responses in vitro and in vivo force the need for basic and animal studies before heading to the clinic. Contrasting reports on immunomodulatory functions and tumorigenicity along with issues such as mode of cell delivery, lack of specific marker, low survival and engraftment require urgent attention to harness the potential of MSC-based therapy in the near future.
Mesenchymal stem cells (MSCs) represent an adherent, fibroblast-like population present not only in the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis. Their extensive proliferation and transdifferentiation potential makes them best suited for tissue engineering applications. Identification of growth factors and signaling pathways involved in self-renewal and differentiation is important for designing strategies to overcome replicative senescence and attain directed differentiation. Wnt, bone morphogenetic protein (BMP), and Notch pathways have been implicated to play key roles in self-renewal and differentiation of hematopoietic, intestinal, and epidermal stem cells. They are also involved in regulating MSC differentiation. However, MSC self-renewal has not received much attention, with Nucleostemin being the only recently identified proliferation molecule. Although immortalization using viral oncogenes and telomerase has been achieved, transformation in long-term cultures is a potential risk. Understanding of the mechanisms governing osteogenic differentiation of MSCs is expanding with the recent identification of two major transcription factors, Osterix and Runx2. Enhanced expansion as well as osteogenic differentiation of MSCs can be attained using a combinatorial approach involving co-expression of proliferation and differentiation genes. However, a thorough understanding of the molecular mechanism is necessary for enhancing the self-renewal ability and osteogenic potential in vitro.
Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major determining factor in success of hematopoietic stem cell transplantation. This is a complex, multistep process orchestrated by the coordinated interplay between adhesion molecules, cytokines, growth factors, and regulatory cofactors, many of which remain to be defined. Recent studies have highlighted the pivotal role of unique stromal-derived factor-1 (SDF-1)/CXCR4 signaling in the regulation of HSPC homing and subsequent engraftment. In addition, studies suggest that SDF-1/CXCR4 signaling acts as an essential survival-promoting factor of transplanted HSPCs as well as maintenance of quiescent HSCs in bone marrow niche. These pleiotropic effects exerted by SDF-1/CXCR4 axis make this unique signaling initiator very promising, not only for optimal hematopoietic reconstitution but also for the development of innovative approaches to achieve restoration, regeneration, or repair of other damaged tissues potentially amendable to reversal by stem cell transplantation. This goal can only be achieved when the role of SDF-1/CXCR4 axis in hematopoietic transplantation is clearly defined. Hence, this review presents current knowledge of the mechanisms through which SDF-1/CXCR4 signaling promotes restoration of hematopoiesis by regulating the homing and engraftment of HSPCs.
Human mesenchymal stem cells (hMSCs) present in the bone marrow are the precursors of osteoblasts, chondrocytes and adipocytes, and hold tremendous potential for osteoregenerative therapy. However, achieving directed differentiation into osteoblasts has been a major concern. The use of lithium for enhancing osteogenic differentiation has been documented in animal models but its effect in humans is not clear. We, therefore, performed high throughput transcriptome analysis of lithium-treated hMSCs to identify altered gene expression and its relevance to osteogenic differentiation. Our results show suppression of proliferation and enhancement of alkaline phosphatase (ALP) activity upon lithium treatment of hMSCs under non-osteogenic conditions. Microarray profiling of lithium-stimulated hMSC revealed decreased expression of adipogenic genes (CEBPA, CMKLR1, HSD11B1) and genes involved in lipid biosynthesis. Interestingly, osteoclastogenic factors and immune responsive genes (IL7, IL8, CXCL1, CXCL12, CCL20) were also downregulated. Negative transcriptional regulators of the osteogenic program (TWIST1 and PBX1) were suppressed while genes involved in mineralization like CLEC3B and ATF4 were induced. Gene ontology analysis revealed enrichment of upregulated genes related to mesenchymal cell differentiation and signal transduction. Lithium priming led to enhanced collagen 1 synthesis and osteogenic induction of lithium pretreated MSCs resulted in enhanced expression of Runx2, ALP and bone sialoprotein. However, siRNA-mediated knockdown of RRAD, CLEC3B and ATF4 attenuated lithium-induced osteogenic priming, identifying a role for RRAD, a member of small GTP binding protein family, in osteoblast differentiation. In conclusion, our data highlight the transcriptome reprogramming potential of lithium resulting in higher propensity of lithium “primed” MSCs for osteoblastic differentiation.
To conclude, we will briefly discuss the current problems that hinder bench to bedside translation of iPSC research as well as the possible steps that can bring iPSC therapy and other potential applications closer to fruition.
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