The engineering of bone using osteoprogenitor cells has enormous clinical potential for the treatment of many bony defects including a wide range of congenital bone defects, including alveolar cleft defects. Recent work has concentrated on the combination of progenitor cells with solid, three-dimensional support structures such as scaffolds in order to induce bone healing in animal model systems. Stem cells have come to represent a viable source for osteoprogenitor cells in these types of applications. Therefore, the long-range objective of this grant is the development of innovative, new treatments for human bone loss through the use of stem cells and tissue engineering techniques. Recent data has confirmed the presence of a putative stem cell population within adipose tissue - termed adipose-derived stem cells (ASCs) - possessing osteogenic potential. Preliminary data suggests that stem cells like ASCs may be capable of osteogenic differentiation in vivo and therefore able to initially heal bony defects. Current strategies for inducing stem cells to form bone in vivo involve their treatment with growth factors such as BMP2. However, when healing craniofacial defects in young children (i.e. under 6 years), the use of BMPs may not be possible due to increased incidence of ectopic bone formation. This would suggest that an alternate mechanism for stimulating ASCs to make bone in vivo will be necessary. In the formation of bone, preliminary microarray analysis of ASCs has suggested that ERK kinases may be involved in mediating differentiation of ASCs into the osteogenic lineage. Based on this, our central hypothesis is that the kinases of the MAPK pathway may be able to promote the in vivo osteogenic capacity of ASCs without the need for exogenous growth factors.
The specific aims outlined in this application are: (1) to characterize the role of the MAPK signal transduction pathway in ASCs during osteogenesis in vitro, (2) to enhance the in vivo osteogenic capacity of ASCs through manipulation of this MAPK signaling pathway and 3) to develop a novel in vivo adhesion-driven mechanism that affects the MAPK signaling pathway in ASCs in such a way to promote bony healing by these stem cells without the need for exogenous growth factors. ? ? ?
| Chou, Yu-Fen; Zuk, Patricia A; Chang, Ting-Ling et al. (2011) Adipose-derived stem cells and BMP2: part 1. BMP2-treated adipose-derived stem cells do not improve repair of segmental femoral defects. Connect Tissue Res 52:109-18 |
| Zuk, Patricia; Chou, Yu-Fen; Mussano, Federico et al. (2011) Adipose-derived stem cells and BMP2: part 2. BMP2 may not influence the osteogenic fate of human adipose-derived stem cells. Connect Tissue Res 52:119-32 |
