Activated cardiac fibroblasts are a primary source of high-molecular-weight hyaluronan production

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 HAS2. 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 Has2 mRNA and concomitant accumulation of hyaluronan >1 MDa in size. Deletion of Has2 abrogated TGFβ-induced production of hyaluronan. In addition, overexpression of Has2 was sufficient to cause an increase in hyaluronan accumulation in the absence of TGFβ-induced activation. Our data indicated negligible impacts of Has2 on proliferation, migration, and collagen production. Exposing fibroblasts to exogenous hyaluronan also had minimal impact on fibroblasts. We also assessed whether fibroblast-borne Hyal2 plays a role in the degradation of hyaluronan, and our data indicated little impact of Hyal2 on hyaluronan accumulation (or even any impacts on the transcriptional profile of fibroblasts). Activated fibroblasts produce high-molecular-weight hyaluronan via Has2, which occurs independent of other fibroblast functions.NEW & NOTEWORTHY 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.