Hypoxic-Normoxic Crosstalk Activates Pro-Inflammatory Signaling in Human Cardiac Fibroblasts and Myocytes in a Post-Infarct Myocardium on a Chip

被引：2

作者：

Khalil, Natalie N. ^{[1
]}

Rexius-Hall, Megan L. ^{[1
]}

Gupta, Divya ^{[2
,3
]}

Mccarthy, Liam ^{[2
,3
]}

Verma, Riya ^{[4
]}

Kellogg, Austin C. ^{[1
]}

Takamoto, Kaelyn ^{[1
]}

Xu, Maryann ^{[1
]}

Nejatpoor, Tiana ^{[1
]}

Parker, Sarah J. ^{[2
,3
]}

Mccain, Megan L. ^{[1
,4
]}

机构：

[1] Univ Southern Calif, USC Viterbi Sch Engn, Alfred E Mann Dept Biomed Engn, Los Angeles, CA 90089 USA

[2] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA

[3] Cedars Sinai Med Ctr, Smidt Heart Inst, Los Angeles, CA 90048 USA

[4] Univ Southern Calif, Keck Sch Med USC, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA

来源：

ADVANCED HEALTHCARE MATERIALS | 2024年 / 13卷 / 28期

关键词：

cardiac fibrosis; crosstalk; hypoxia; myocardial infarction; organ-on-a-chip; MICROPHYSIOLOGICAL DEVICES; FACTOR-ALPHA; STEM-CELLS; FIBROSIS; MODEL; DYNAMICS; INJURY; REPAIR; PROLIFERATION; INTERLEUKIN-6;

D O I：

10.1002/adhm.202401478

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

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-alpha). 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. Myocardial infarctions are typically followed by a pathological fibrotic remodeling process that is potentially orchestrated by crosstalk between healthy and injured tissue. Here, a post-infarct myocardium on a chip is engineered to enable crosstalk between hypoxic cardiac fibroblasts and normoxic cardiac fibroblasts or myocytes. This system demonstrates that hypoxic-normoxic crosstalk exacerbates pro-inflammatory signaling pathways in cardiac cells. image

引用

页数：15