Little Danielle T, Howard Caitlin M, Pendergraft Emma, Brittian Kenneth R, Audam Timothy N, Lukudu Exile W, Smith Juliette, Nguyen Daniel, Nishida Yoshihiro, Yamaguchi Yu, Brainard Robert E, Singhal Richa A, Jones Steven P
Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, University of Louisville, Louisville, Kentucky, United States.
Department of Orthopedic Surgery, Nagoya University, Nagoya, Japan.
Am J Physiol Cell Physiol. 2025 Mar 1;328(3):C939-C953. doi: 10.1152/ajpcell.00786.2024. Epub 2025 Jan 27.
During acute myocardial infarction, the composition of the extracellular matrix changes remarkably. One of the most notable changes in the extracellular matrix is in the accumulation of collagen; however, hyaluronan rivals collagen in its abundance. Yet, the extent to which specific cells and enzymes may contribute to such accumulation has been largely unexplored. Here, we hypothesized that activated cardiac fibroblasts produce hyaluronan via hyaluronan synthase 2 (HAS2). We show that hyaluronan accumulates following myocardial infarction and persists through at least 4 wk. Our analyses of failing heart RNA sequencing data suggest that fibroblasts are the cells most changed in the expression of . Given these insights, we used HAS2 gain- and loss-of-function approaches to examine the extent to which activated cardiac fibroblasts produce hyaluronan. Transforming growth factor β (TGFβ)-induced activation of fibroblasts caused a significant increase in mRNA and concomitant accumulation of hyaluronan >1 MDa in size. Deletion of abrogated TGFβ-induced production of hyaluronan. In addition, overexpression of was sufficient to cause an increase in hyaluronan accumulation in the absence of TGFβ-induced activation. Our data indicated negligible impacts of on proliferation, migration, and collagen production. Exposing fibroblasts to exogenous hyaluronan also had minimal impact on fibroblasts. We also assessed whether fibroblast-borne plays a role in the degradation of hyaluronan, and our data indicated little impact of on hyaluronan accumulation (or even any impacts on the transcriptional profile of fibroblasts). Activated fibroblasts produce high-molecular-weight hyaluronan via , which occurs independent of other fibroblast functions. Activated cardiac fibroblasts produce copious quantities of collagen, and much is known about this process. They also produce hyaluronan, which is abundant in the extracellular matrix, but less is known about hyaluronan. Here, we identify cardiac fibroblasts as major producers of hyaluronan and, specifically, that they produce high-molecular-weight hyaluronan via HAS2. This has important implications for ventricular remodeling and for metabolic regulation of activated fibroblasts, as they produce this abundant matrix component.
在急性心肌梗死期间，细胞外基质的组成会发生显著变化。细胞外基质中最显著的变化之一是胶原蛋白的积累；然而，透明质酸在数量上可与胶原蛋白相媲美。然而，特定细胞和酶对这种积累的贡献程度在很大程度上尚未得到探索。在此，我们假设活化的心脏成纤维细胞通过透明质酸合酶2（HAS2）产生透明质酸。我们发现透明质酸在心肌梗死后会积累，并至少持续4周。我们对衰竭心脏RNA测序数据的分析表明，成纤维细胞是基因表达变化最大的细胞。基于这些见解，我们使用HAS2功能获得和功能缺失方法来研究活化的心脏成纤维细胞产生透明质酸的程度。转化生长因子β（TGFβ）诱导的成纤维细胞活化导致mRNA显著增加，并伴随大于1 MDa大小的透明质酸积累。删除该基因可消除TGFβ诱导的透明质酸产生。此外，在没有TGFβ诱导活化的情况下，该基因的过表达足以导致透明质酸积累增加。我们的数据表明该基因对增殖、迁移和胶原蛋白产生的影响可忽略不计。将成纤维细胞暴露于外源性透明质酸对成纤维细胞的影响也很小。我们还评估了成纤维细胞产生的该基因是否在透明质酸降解中起作用，我们的数据表明该基因对透明质酸积累的影响很小（甚至对成纤维细胞的转录谱没有任何影响）。活化的成纤维细胞通过该基因产生高分子量透明质酸，这一过程独立于其他成纤维细胞功能。活化的心脏成纤维细胞会产生大量胶原蛋白，对此过程已有很多了解。它们还产生透明质酸，透明质酸在细胞外基质中含量丰富，但对其了解较少。在此，我们确定心脏成纤维细胞是透明质酸的主要产生者，具体而言，它们通过HAS2产生高分子量透明质酸。这对心室重塑以及活化成纤维细胞的代谢调节具有重要意义，因为它们产生了这种丰富的基质成分。
