HEMATOPOIETIC STEM CELLS IN CARDIOVASCULAR REGENERATIVE MEDICINE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的初步研究，使用谱系标记(EGFP)的骨髓，证明了造血干细胞对心脏成纤维细胞群的贡献，基于我们的发现，在梗死心肌中，HSC来源的细胞亚群表达DDR2并合成I型胶原。这些HSC来源的细胞密集分布在受损的心肌中，可能被用来调节梗死后心肌的病理性重构程度。 拟议的研究将确定HSC来源的心脏成纤维细胞在梗死后瘢痕形成和心功能中的分子和生化贡献，并将这些细胞生物学行为与常驻心脏成纤维细胞进行比较。拟议的实验还将检验移植到心肌中的HSC来源细胞数量的调节对心肌梗死的反应，以及Periostin信号调节对梗死区HSC来源细胞成纤维细胞分化的影响。有三个目标： A)为了验证HSC来源的成纤维细胞(HSC-f)参与心肌梗死后心室重构的假说，我们将对心肌梗死后成纤维细胞特异性mRNA和蛋白的表达、细胞增殖率和死亡率以及HSC-f的谱系分析进行综合分析。 B)为了验证HSC-f移植到梗死区心肌组织后影响梗死后心功能和病理重塑的假说，我们将通过心功能、抗张强度和组织重塑的分析来评估HSC移植小鼠心肌梗死和骨髓动员的调节作用。 C)验证基质细胞蛋白Periostin是移植到梗死后瘢痕中的HSC来源的细胞向成纤维细胞分化的活跃效应的假设。我们将对移植了PN-/-骨髓HSCs的野生型小鼠(与野生型HSCs相比)进行成纤维细胞特异性的mRNA和蛋白表达、体内纤维化反应和心功能分析，以确定PN表达的调节在急性和慢性心肌病理重塑中的作用。

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.