Major signaling pathways regulating the proliferation and differentiation of mesenchymal stem cells

Abstract

Various highly regulated, complex signaling pathways govern the lineage-specific differentiation of mesenchymal stem cells (MSCs). The unique properties of MSCs have allowed us to characterize the differentiation pathways and proliferative stimuli of these lineages. While the specific signaling cascades controlling differentiation and proliferation are unique among each lineage, some pathways are critical in the differentiation of multiple lineages. Furthermore, a considerable amount of crosstalk exists between the major signaling pathways. The TGF-β superfamily has significant effects on proliferation and differentiation, including key roles in osteogenic and chondrogenic differentiation. Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily with well-described effects on osteogenesis and chondrogenesis. Demonstrating crosstalk with BMPs, other signaling pathways implicated in osteogenic and chondrogenic differentiation include the Wnt signaling pathway and the FGF family. Hedgehog and notch signaling also crosstalk with Wnts, with diverse effects on osteogenic, myogenic and adipogenic differentiation. PPARγ is the master regulator of adipogenesis and is essential for the induction of normal adipogenesis, and C/EBPs modulate the expression and function of PPARγ. Crosstalk exists between the major signaling pathways governing adipogenesis and osteogenesis, as differential expression of BMPs and PPARγ significantly alters adipogenic and osteogenic differentiation. While the major signaling pathways mediating lineage-specific differentiation are well-studied, the complex crosstalk between these pathways and lineage-specific cascades makes elucidation of specific mechanisms quite difficult.