Activated Cardiac Fibroblasts Are a Primary Source of High-molecular-weight Hyaluronan Production.

Details

• Alternative Title:
  American Journal of Physiology. Cell Physiology, 2025, v. 328, no. 3: Activated Cardiac Fibroblasts Are a Primary Source of High-molecular-weight Hyaluronan Production.
• Journal Article:
  American Journal of Physiology. Cell Physiology
• Personal Author:
  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.
• Description:
  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.
• Content Notes:
  Author manuscript
• Subjects:
  • Hyaluronic Acid
  • Animals
  • Hyaluronan Synthases
  • Fibroblasts
  • Myocardium
  • Myocardial Infarction
  • Mice
  • Molecular Weight
  • Transforming Growth Factor beta
  • Extracellular Matrix
  More +
• Keywords:
  • Fibrosis
  • Extracellular Matrix
  • Heart Failure
  • Myocardial Infarction
• Source:
  American Journal of Physiology. Cell Physiology, 2025, v. 328, no. 3
• DOI:
  https://doi.org/10.1152/ajpcell.00786.2024
• ISSN:
  0363-6143 ; 1522-1563
• Pubmed ID:
  39871135
• Pubmed Central ID:
  PMC12172657
• Document Type:
  Text
• Funding:
  970338/AHA/American Heart Association-American Stroke AssociationUnited States/ ; 916776/AHA/American Heart Association-American Stroke AssociationUnited States/ ; R01 HL147844/HL/NHLBI NIH HHSUnited States/ ; P30 GM127607/GM/NIGMS NIH HHSUnited States/ ; R01 GM127495/GM/NIGMS NIH HHSUnited States/ ; R01 HL 163272/HHS ; NIH ; National Heart, Lung, and Blood Institute (NHLBI)/ ; S10 OD025178/OD/NIH HHSUnited States/ ; R01 HL163272/HL/NHLBI NIH HHSUnited States/ ; Jewish Heritage Fund for Excellence/ ; S10 OD025178/CD/ODCDC CDC HHSUnited States/ ; F31 HL162518/HL/NHLBI NIH HHSUnited States/
• Genre:
  Journal Article
• Pages in Document:
  C939-C953 (27 pdf pages)
• Volume:
  328
• Issue:
  3
• Download URL:
  https://stacks.cdc.gov/view/cdc/261732/cdc_261732_DS1.pdf
• File Type:
  [PDF - 1.50 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:b062c0d10e3662dbae0ef865f3322984646f05bbfb5a5b1e2cd13fa76e783c6f721d7e16755baad8300317bf1b5c0295bed5e76f79b9a65c87c00ece65d48c2a