Department of Animal Biology, Faculty of Sciences, University of Málaga, Málaga, Spain; Department of Anatomy, Embryology and Physiology, AMC-University of Amsterdam, Amsterdam, the Netherlands.
Department of Hematology, Clínica Universitaria de Navarra-CIMA, Universidad de Navarra, Pamplona, Spain.
J Am Coll Cardiol. 2015 May 19;65(19):2057-66. doi: 10.1016/j.jacc.2015.03.520.
Although efforts continue to find new therapies to regenerate infarcted heart tissue, knowledge of the cellular and molecular mechanisms involved remains poor.
This study sought to identify the origin of cardiac fibroblasts (CFs) in the infarcted heart to better understand the pathophysiology of ventricular remodeling following myocardial infarction (MI).
Permanent genetic tracing of epicardium-derived cell (EPDC) and bone marrow-derived blood cell (BMC) lineages was established using Cre/LoxP technology. In vivo gene and protein expression studies, as well as in vitro cell culture assays, were developed to characterize EPDC and BMC interaction and properties.
EPDCs, which colonize the cardiac interstitium during embryogenesis, massively differentiate into CFs after MI. This response is disease-specific, because angiotensin II-induced pressure overload does not trigger significant EPDC fibroblastic differentiation. The expansion of epicardial-derived CFs follows BMC infiltration into the infarct site; the number of EPDCs equals that of BMCs 1 week post-infarction. BMC-EPDC interaction leads to cell polarization, packing, massive collagen deposition, and scar formation. Moreover, epicardium-derived CFs display stromal properties with respect to BMCs, contributing to the sustained recruitment of circulating cells to the damaged zone and the cardiac persistence of hematopoietic progenitors/stem cells after MI.
EPDCs, but not BMCs, are the main origin of CFs in the ischemic heart. Adult resident EPDC contribution to the CF compartment is time- and disease-dependent. Our findings are relevant to the understanding of post-MI ventricular remodeling and may contribute to the development of new therapies to treat this disease.
尽管人们一直在努力寻找新的疗法来再生梗死的心脏组织，但对涉及的细胞和分子机制仍知之甚少。
本研究旨在确定梗死心脏中心房成纤维细胞（CFs）的来源，以更好地了解心肌梗死后心室重构的病理生理学。
利用 Cre/LoxP 技术建立了心脏外胚层衍生细胞（EPDC）和骨髓源性血细胞（BMC）谱系的永久遗传示踪。开展了体内基因和蛋白表达研究以及体外细胞培养试验，以鉴定 EPDC 和 BMC 之间的相互作用和特性。
胚胎发生期间定殖于心外膜间隙的 EPDC 在 MI 后大量分化为 CFs。这种反应是疾病特异性的，因为血管紧张素 II 诱导的压力超负荷不会引发明显的 EPDC 成纤维细胞分化。心外膜衍生的 CFs 的扩张是伴随着 BMC 浸润梗死部位而发生的；梗死后 1 周，EPDC 的数量与 BMC 相等。BMC-EPDC 相互作用导致细胞极化、包裹、大量胶原沉积和瘢痕形成。此外，心外膜衍生的 CFs 具有与 BMC 相关的基质特性，有助于循环细胞持续募集到损伤区域，并使造血祖细胞/干细胞在 MI 后在心内持续存在。
EPDC 而不是 BMC 是缺血心脏中 CFs 的主要来源。成年常驻 EPDC 对 CF 区室的贡献是时间和疾病依赖性的。我们的发现与理解 MI 后心室重构有关，可能有助于开发治疗这种疾病的新疗法。
