Wound repair involves the orchestration of multiple cellular events, including the proliferation and migration of terminally differentiated indigenous cells, such as keratinocytes, fibroblasts and endothelial cells. In adult skin, wound healing recreates an adapted epithelium that lacks epidermal appendages and generates a variably collagen-rich, contracted dermis. The underlying problem is that adult cutaneous wounds heal by repair, rather than by regeneration. Methods to promote adult cutaneous tissue regeneration are needed. The skin and bone marrow (BM) harbor undifferentiated epithelial and mesenchymal cell types, respectively that could provide the regenerative cellular components in response to cutaneous injury. Our preliminary data show that BM derived cells do populate the healing wound to provide epithelial and dermal cell types. These observations must be further evaluated to determine the differentiation signal(s) that may regulate the fate of skin and BM-derived cells in the wound. Undifferentiated cells respond to morphogens, which are families of signaling proteins that determine cell fate. One of these families, the Wnt genes, are crucial effectors of cell fate determination during development and activate gene transcription by two pathways, one that is dependent on the accumulation of free b-catenin (Wnt/ b-catenin pathway) and the other that is dependent on intracellular Ca2+ and protein kinase C (Wnt/Ca2+ pathway). Our preliminary data shows that Wnt genes have marked regenerative effects in vivo following wounding. We propose to determine the roles of BM-derived cells and Wnt genes in adult cutaneous wound repair. Our hypotheses are that during wound repair morphogenesis, the Wnt/ b-catenin pathway regulates epidermal cell fate and epidermal regeneration and the Wnt/ Ca2+ pathway regulates mesenchymal cell fate and dermal regeneration. We will test our hypotheses with the following specific aims: 1. To determine the contribution of bone marrow-derived cells to wound repair and regeneration. 2. To determine whether Wnt signaling regulates differentiation of BM-derived and wound resident cells. 3. To determine whether activating or blocking the Wnt pathways alters wound repair and regeneration.
| Fathke, Carrie; Wilson, Lynne; Shah, Kavita et al. (2006) Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol 7:4 |
| Fathke, Carrie; Wilson, Lynne; Hutter, Jonathan et al. (2004) Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells 22:812-22 |
