Microenvironmental control of progenitors in organ dysfunction and repair

描述(由申请人提供)： 这项提议的核心是，间充质细胞是组织发育、维护和修复的必要参与者，并且将是实现再生医学中重新编程细胞的全部潜力所必需的。利用细胞重编程的进展将取决于对细胞状态如何指定、细胞如何组织成复杂模式以及异型细胞在生理应激期间如何相互作用的深入理解。对这些过程的细胞自主观点是不充分的，可以通过充分阐明组织特异性间充质细胞所起的贡献作用来补充。根据发展的经验教训，很明显，间充质细胞是建立组织的基础，改变特定细胞类型的增殖、分化和模式。然而，间充质种群在它们的复杂性、血统关系和调节其功能的调控途径方面仍然是个谜。这项建议试图通过召集一组具有互补优势的研究人员来解决这一不足，这些研究人员拥有高生产率和协作性科学的记录。具体目标如下：1.确定包括骨髓、肺和心脏器官基质的间充质谱系。将应用先前定义的在体内分离、分子和功能表征以及解剖定位细胞群体的方法，并进行比较2.确定微环境如何通过改变基质细胞和祖细胞之间的相互作用来完成其调控。基质细胞和祖细胞群体之间的相互作用将通过遗传和小分子操作来改变。3.与其他联合体参与者互动，评估基质成分在诱导多能细胞(IPS)背景下影响谱系分化和祖细胞功能的能力。这些目标的成功实现将对该联盟以祖细胞为重点的方面提供补充，从而使以组织为基础的再生医学方法成为可能。

DESCRIPTION (provided by applicant): 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.