| Multi-potent stem cell populations found in adult tissues have been of great interest because they serve as reservoirs for tissue renewal after trauma, disease and aging. One important type of adult stem cell derived from bone marrow is the mesenchymal stem cell (MSC), which contributes to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, tendon and adipose (Pittenger et al. 1999 Caplan 2005). However, lack of knowledge at the molecular level on the regulatory mechanisms underlying the self-renewal and differentiation of MSCs has limited the potential use of MSCs in practical applications such as tissue engineering and gene therapy (Caplan 2000b Caplan and Bruder 2001).In this thesis we describe a novel form of crosstalk between the TGF-beta and Wnt signaling pathways and its functional role in regulating the proliferation and osteouenic differentiation of human MSCs. We show that TGF-beta induces rapid nuclear translocation of beta-catenin in MSCs in a Wnt signaling-independent fashion. TGF-beta does not affect the stability of beta-catenin, but requires the activity of the TGF-beta type I receptor and the presence of Smad3. Functionally, this pathway is required for the stimulation of MSC proliferation and the inhibition of MSC osteogenic differentiation by TGF-beta likely through the combined actions of beta-catenin and Smad3 to regulate downstream target genes. These results provide evidence for a novel mode of cooperation between the TGF-beta and Wnt signaling pathways in this specific cellular context, and suggest a potentially important role for this distinct signaling pathway in the control of self-renewal and differentiation of mesenchymal stem cells. |
