The central tenant of this proposal is that mesenchymal cells are necessary participants in tissue development, maintenance and repair and will be required for realization of the full potential of reprogrammed cells in regenerative medicine. Efforts to exploit the advance of cell reprogramming will depend upon in-depth understanding of how cell state is specified, how the cells organize into complex patterns and how heterotypic cells interrelate during times of physiologic stress. A cell autonomous perspective on these processes is inadequate and can be complemented by full elucidation of the contributory role tissue specific mesenchymal cells play. Based on lessons from development, it is clear that mesenchymal cells are fundamental for establishing the organization of a tissue, altering the proliferation, differentiation and patterning of specific cell types. Yet mesenchymal populations remain enigmatic in terms of their complexity, their lineage relationships and the regulatory pathways that mediate their functions. This proposal seeks to address this deficiency by assembling a group of investigators with complementary strengths who have a record of highly productive and collaborative science. The following specific aims will be addressed: 1. define mesenchymal lineages comprising organ stroma in marrow, lung and heart. Previously defined methods of isolating, molecularly and functionally characterizing and anatomically localizing cell populations in vivo will be applied and comparisons performed 2. Define how the microenvironment accomplishes its regulatory control by modifying the interactions of stromal cells and progenitor cells. Interactions between stromal and progenitor cell populations will be modified by genetic and small molecule manipulations. 3. Interact with other Consortium participants to evaluate the ability of stromal constituents to affect lineage differentiation and progenitor function in the context of induced pluripotent cells (iPS). Successful accomplishment of these aims will provide a complement to progenitor focused aspects of the Consortium and thereby enable a tissue-based approach to regenerative medicine.
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