From cancer to heart fibrosis - GLIPR1 highlights a subset of myofibroblasts responsive to mesenchymal stem cell therapy after myocardial infarction

Abstract Despite recent advances in pre-clinical research on cardiac remodeling following myocardial infarction (MI), the precise molecular pathways remain poorly understood and effective therapies for heart failure are still delayed in development. Aged animal models may more accurately reflect the clinical scenario, as aging alters the cellular identities and impedes cardiac repair. In this manuscript, we investigated the expression profile of mouse cardiac fibroblasts following myocardial infarction, using both young and aged animals to enhance the translational significance. The initial studies aimed to identify fibroblast changes common to both young and old animals. Additionally, a group of young animals that underwent mesenchymal stem cells (MSC) therapy after MI surgery was included to help identify the molecular changes amenable to therapeutic modulation. The analysis uncovered Glioma- Pathogenesis Related Protein 1 (GLIPR1) activation during the post-MI maturation phase in a subset of myofibroblasts, localized to the infarct zone in young subjects and widespread throughout the ventricle in aged animals. Further investigations indicated that the inflammatory environment post-MI induced the upregulation of GLIPR1, which in turn promoted increased TIMP3 expression. These findings provide valuable insights for future research aimed at exploring the therapeutic potential of targeting GLIPR1 to reduce cardiac fibrosis post-MI. Keywords: Aged mice; Cardiac fibroblast; GLIPR1; MSC therapy; Myocardial infarction; RNA-sequencing.摘要 尽管目前在心肌梗死（Myocardial Infarction，MI）后心脏重构的临床前研究领域已取得一定进展，但确切的分子通路仍未被充分阐明，心力衰竭的有效治疗手段研发仍进展迟缓。由于衰老会改变细胞特性并阻碍心脏修复，老年动物模型可更精准地模拟临床场景。本文以年轻及老年小鼠为研究对象，探究了心肌梗死后小鼠心脏成纤维细胞的表达谱，以提升研究的转化价值。本研究的初始目标为鉴定年轻与老年小鼠共有的成纤维细胞变化；此外，本研究还纳入了一组在心肌梗死手术后接受间充质干细胞（MSC）治疗的年轻小鼠，以助力识别可被治疗调控的分子变化。分析结果显示，在心肌梗死后成熟阶段，部分肌成纤维细胞中存在胶质瘤致病相关蛋白1（GLIPR1）的激活：该蛋白在年轻小鼠的梗死区域呈局限性表达，而在老年动物中则广泛分布于心室全层。进一步研究表明，心肌梗死后的炎症微环境可诱导GLIPR1的上调，而GLIPR1进而促进了金属蛋白酶组织抑制剂3（TIMP3）的表达升高。本研究结果为未来探索以GLIPR1为靶点以减轻心肌梗死后心脏纤维化的治疗潜力提供了重要参考。 关键词：老年小鼠；心脏成纤维细胞；GLIPR1；间充质干细胞治疗；心肌梗死；RNA测序（RNA-Sequencing）