Mesenchymal Stem Cells: Molecular Targets for Tissue Engineering

Abstract

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.

Telomerase reverse transcriptase mediated immortalization of human bone marrow stromal cells

“…MSCs are also known as marrow stromal stem cells and marrow mesenchymal stem cells (Richardson et al 2010;Zellner et al 2010 (Satija et al 2007). In several studies, exogenous virus, or oncogene has been introduced to target the cells to construct the immortalized cells (Kelekar and Cole 1987;Arimura et al 2007;Wu et al 2007), in which the integration of target gene was random and expression of target gene might have interfered with the intracellular physiological processes, which could result in unexpected changes such as loss of differentiation characteristic and lack of control of check point.…”

sFRP2 Suppression of Bone Morphogenic Protein (BMP) and Wnt Signaling Mediates Mesenchymal Stem Cell (MSC) Self-renewal Promoting Engraftment and Myocardial Repair

“…Self-renewal is an intrinsic property of stem cells that allows them to give rise to non-differentiated daughter cells by proliferating, preventing apoptosis, and avoid lineage commitment (5,6). This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound.…”

“…This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound. Although several cytokines, growth factors, adhesion molecules, and extracellular matrix components have been identified as cues that signal MSCs to differentiate, the molecular signals that modulate MSC self-renewal remain unknown (5). Data from the hematopoietic stem cell (HSC) field have documented the involvement of Wnt, Notch, and BMP signaling cascades in self-renewal; these pathways are implicated in the expansion of undifferentiated HSCs that upon transplantation into lethally irradiated mice successfully reconstitute the cleared bone marrow (7)(8)(9).…”

Protein Expression Profiles during Osteogenic Differentiation of Mesenchymal Stem Cells Derived from Human Umbilical Cord Blood

“…Differentiation of MSCs is an ordered process that proceeds stepwise through cell proliferation, differentiation, formation of extracellular matrix and mineralization stages (Marie and Fromigue 2006;Satija et al 2007). Kulterer et al (2007), using an oligonucleotide microarray-based gene expression analysis, demonstrated a specific time scale for the in vitro differentiation of BM-MSCs: proliferation phase (0-4 days), matrix maturation phase (4-14 days) and mineralization phase (14-21 days).…”