This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our preliminary studies, using lineage-marked (EGFP+) bone marrow, demonstrate that there is hematopoietic stem cell contribution to the cardiac fibroblast population, based on our findings that a sub-population of HSC-derived cells express DDR2 and synthesize collagen type I in the infarcted myocardium. These HSC-derived cells, which densely populate the damaged myocardium, could possibly be used to modulate the degree of pathological remodeling in the post-infarction myocardium. Proposed studies will define the molecular and biochemical contribution of HSC-derived cardiac fibroblasts to post-infarction scar formation and cardiac function, and compare these cell biological behaviors to those of resident cardiac fibroblasts. Proposed experiments will also examine the effects of modulation of numbers of HSC-derived cells that engraft into the myocardium in response to infarction as well as the effects of modulation of periostin signaling on the fibroblastic differentiation of HSC-derived cells that home to the infarct zone. There are three aims: a) to test the hypothesis that HSC-derived fibroblasts (HSC-f) participate in post-infarction ventricular remodeling, we will perform comprehensive analysis of expression of post-infarction fibroblast-specific mRNA and protein, rates of proliferation and death, and lineage analysis of HSC-fs. b) to test the hypothesis that modulation of HSC-f engraftment into the infarcted cardiac tissue influences post-infarction cardiac function and pathological remodeling, analysis of cardiac function, tensile strength, and tissue remodeling will be performed to evaluate the effects of myocardial infarction combined with modulation of bone marrow mobilization in HSC-transplanted mice. c) to test the hypothesis that the matricellular protein periostin is an active effector of fibroblastic differentiation by HSC-derived cells that engraft into the post-infarction scar. Fibroblast-specific mRNA and protein expression, in vivo fibrogenic response and cardiac functional analyses will be performed in wild-type mice engrafted with PN-/- bone marrow HSCs (vs. wild type HSCs) and subjected to MI to determine the effects of modulation of PN expression on acute and chronic pathological remodeling of the myocardium.
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