Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
J Cell Sci. 2023 Dec 1;136(23). doi: 10.1242/jcs.261152. Epub 2023 Dec 15.
Matrix remodeling outcomes largely dictate patient survival post myocardial infarction. Moreover, human-restricted noncoding regulatory elements have been shown to worsen fibrosis, but their mechanism of action remains elusive. Here, we demonstrate, using induced pluripotent stem cell-derived cardiac fibroblasts (iCFs), that inflammatory ligands abundant in the remodeling heart after infarction activate AP-1 transcription factor signaling pathways resulting in fibrotic responses. This observed signaling induces deposition of fibronectin matrix and is further capable of supporting immune cell adhesion; pathway inhibition blocks iCF matrix production and cell adhesion. Polymorphisms in the noncoding regulatory elements within the 9p21 locus (also referred to as ANRIL) redirect stress programs, and in iCFs, they transcriptionally silence the AP-1 inducible transcription factor GATA5. The presence of these polymorphisms modulate iCF matrix production and assembly and reduce cell-cell signaling. These data suggest that this signaling axis is a critical modulator of cardiac disease models and might be influenced by noncoding regulatory elements.
基质重构的结果在很大程度上决定了心肌梗死后患者的生存情况。此外，已经证明人类特有的非编码调控元件会加重纤维化，但它们的作用机制仍不清楚。在这里，我们利用诱导多能干细胞衍生的心肌成纤维细胞（iCFs）证明，在梗死后心脏重构过程中大量存在的炎症配体激活了 AP-1 转录因子信号通路，从而导致纤维化反应。这种观察到的信号诱导了纤维连接蛋白基质的沉积，并且能够进一步支持免疫细胞的黏附；通路抑制可阻止 iCF 基质的产生和细胞黏附。9p21 基因座（也称为 ANRIL）内非编码调控元件的多态性改变了应激程序，在 iCFs 中，它们转录沉默了 AP-1 诱导的转录因子 GATA5。这些多态性的存在调节 iCF 基质的产生和组装，并减少细胞间信号传递。这些数据表明，该信号轴是心脏疾病模型的关键调节剂，可能受到非编码调控元件的影响。
