Abstract：
Myocardial infarctions locally deprive myocardium of oxygenated blood and cause immediate cardiac myocyte necrosis. Irreparable myocardium is then replaced with a scar through a dynamic repair process that is an interplay between hypoxic cells of the infarct zone and normoxic cells of adjacent healthy myocardium. In many cases, unresolved inflammation or fibrosis occurs for reasons that are incompletely understood, increasing the risk of heart failure. Crosstalk between hypoxic and normoxic cardiac cells is hypothesized to regulate mechanisms of repair after a myocardial infarction. To test this hypothesis, microfluidic devices are fabricated on 3D printed templates for co-culturing hypoxic and normoxic cardiac cells. This system demonstrates that hypoxia drives human cardiac fibroblasts toward glycolysis and a pro-fibrotic phenotype, similar to the anti-inflammatory phase of wound healing. Co-culture with normoxic fibroblasts uniquely upregulates pro-inflammatory signaling in hypoxic fibroblasts, including increased secretion of tumor necrosis factor alpha (TNF-α). In co-culture with hypoxic fibroblasts, normoxic human induced pluripotent stem cell (hiPSC)-derived cardiac myocytes also increase pro-inflammatory signaling, including upregulation of interleukin 6 (IL-6) family signaling pathway and increased expression of IL-6 receptor. Together, these data suggest that crosstalk between hypoxic fibroblasts and normoxic cardiac cells uniquely activates phenotypes that resemble the initial pro-inflammatory phase of post-infarct wound healing.
摘要：
心肌梗塞局部剥夺心肌的氧合血液，并立即导致心肌细胞坏死。然后通过动态修复过程用疤痕代替可修复的心肌,所述动态修复过程是梗死区的缺氧细胞与相邻健康心肌的常氧细胞之间的相互作用。在许多情况下,未解决的炎症或纤维化发生的原因是不完全了解，增加心力衰竭的风险。假设缺氧和常氧心肌细胞之间的串扰调节心肌梗塞后的修复机制。为了检验这个假设，微流体装置在3D打印模板上制造，用于共培养缺氧和常氧心脏细胞。该系统表明，缺氧驱动人心脏成纤维细胞向糖酵解和促纤维化表型，类似于伤口愈合的抗炎阶段。与常氧成纤维细胞共培养可独特地上调低氧成纤维细胞中的促炎信号,包括肿瘤坏死因子α（TNF-α）的分泌增加。在与低氧成纤维细胞共培养中，常氧人类诱导多能干细胞（hiPSC）衍生的心肌细胞也增加促炎信号，白细胞介素6(IL-6)家族信号通路上调和IL-6受体表达增加。一起,这些数据表明,缺氧成纤维细胞和常氧心肌细胞之间的串扰独特地激活了类似于梗死后伤口愈合的初始促炎阶段的表型.
