低氧-常氧串扰激活芯片上梗死后心肌中人心脏成纤维细胞和肌细胞中的促炎症信号传导。
Hypoxic-Normoxic Crosstalk Activates Pro-Inflammatory Signaling in Human Cardiac Fibroblasts and Myocytes in a Post-Infarct Myocardium on a Chip.
发表日期：2024 Jul 12
作者：
Natalie N Khalil, Megan L Rexius-Hall, Divya Gupta, Liam McCarthy, Riya Verma, Austin C Kellogg, Kaelyn Takamoto, Maryann Xu, Tiana Nejatpoor, Sarah J Parker, Megan L McCain
来源：
Cellular & Molecular Immunology
摘要：
心肌梗塞局部剥夺心肌的含氧血液并导致心肌细胞立即坏死。然后，通过动态修复过程，无法修复的心肌被疤痕所取代，该过程是梗死区缺氧细胞与邻近健康心肌的含氧量正常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的发生原因尚不完全清楚，从而增加了心力衰竭的风险。假设缺氧和常氧心肌细胞之间的串扰可以调节心肌梗塞后的修复机制。为了检验这一假设，在 3D 打印模板上制造了微流体装置，用于共培养低氧和常氧心肌细胞。该系统表明，缺氧会促使人类心脏成纤维细胞进行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独特地上调缺氧成纤维细胞中的促炎信号传导，包括增加肿瘤坏死因子α（TNF-α）的分泌。在与缺氧成纤维细胞共培养时，含氧量正常的人诱导多能干细胞 (hiPSC) 来源的心肌细胞也会增加促炎信号传导，包括白细胞介素 6 (IL-6) 家族信号传导途径的上调和 IL-6 受体表达的增加。总之，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。© 2024 Wiley‐VCH GmbH。
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.© 2024 Wiley‐VCH GmbH.