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hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration.

Publication ,  Journal Article
Sun, J; Peterson, EA; Wang, AZ; Ou, J; Smith, KE; Poss, KD; Wang, J
Published in: Circulation
July 5, 2022

BACKGROUND: Certain nonmammalian species such as zebrafish have an elevated capacity for innate heart regeneration. Understanding how heart regeneration occurs in these contexts can help illuminate cellular and molecular events that can be targets for heart failure prevention or treatment. The epicardium, a mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebrafish. The extent to which different cell subpopulations or states facilitate heart regeneration requires research attention. METHODS: To dissect epicardial cell states and associated proregenerative functions, we performed single-cell RNA sequencing and identified 7 epicardial cell clusters in adult zebrafish, 3 of which displayed enhanced cell numbers during regeneration. We identified paralogs of hapln1 as factors associated with the extracellular matrix and largely expressed in cluster 1. We assessed HAPLN1 expression in published single-cell RNA sequencing data sets from different stages and injury states of murine and human hearts, and we performed molecular genetics to determine the requirements for hapln1-expressing cells and functions of each hapln1 paralog. RESULTS: A particular cluster of epicardial cells had the strongest association with regeneration and was marked by expression of hapln1a and hapln1b. The hapln1 paralogs are expressed in epicardial cells that enclose dedifferentiated and proliferating cardiomyocytes during regeneration. Induced genetic depletion of hapln1-expressing cells or genetic inactivation of hapln1b altered deposition of the key extracellular matrix component hyaluronic acid, disrupted cardiomyocyte proliferation, and inhibited heart regeneration. We also found that hapln1-expressing epicardial cells first emerge at the juvenile stage, when they associate with and are required for focused cardiomyocyte expansion events that direct maturation of the ventricular wall. CONCLUSIONS: Our findings identify a subset of epicardial cells that emerge in postembryonic zebrafish and sponsor regions of active cardiomyogenesis during cardiac growth and regeneration. We provide evidence that, as the heart achieves its mature structure, these cells facilitate hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. They are also required, along with the function of hapln1b paralog, in the production and organization of hyaluronic acid-containing matrix in cardiac injury sites, enabling normal cardiomyocyte proliferation and muscle regeneration.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

July 5, 2022

Volume

146

Issue

1

Start / End Page

48 / 63

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Regeneration
  • Proteoglycans
  • Organogenesis
  • Myocytes, Cardiac
  • Mice
  • Hyaluronic Acid
  • Humans
  • Heart
 

Citation

APA
Chicago
ICMJE
MLA
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Sun, J., Peterson, E. A., Wang, A. Z., Ou, J., Smith, K. E., Poss, K. D., & Wang, J. (2022). hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration. Circulation, 146(1), 48–63. https://doi.org/10.1161/CIRCULATIONAHA.121.055468
Sun, Jisheng, Elizabeth A. Peterson, Annabel Z. Wang, Jianhong Ou, Kieko E. Smith, Kenneth D. Poss, and Jinhu Wang. “hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration.Circulation 146, no. 1 (July 5, 2022): 48–63. https://doi.org/10.1161/CIRCULATIONAHA.121.055468.
Sun J, Peterson EA, Wang AZ, Ou J, Smith KE, Poss KD, et al. hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration. Circulation. 2022 Jul 5;146(1):48–63.
Sun, Jisheng, et al. “hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration.Circulation, vol. 146, no. 1, July 2022, pp. 48–63. Pubmed, doi:10.1161/CIRCULATIONAHA.121.055468.
Sun J, Peterson EA, Wang AZ, Ou J, Smith KE, Poss KD, Wang J. hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration. Circulation. 2022 Jul 5;146(1):48–63.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

July 5, 2022

Volume

146

Issue

1

Start / End Page

48 / 63

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Regeneration
  • Proteoglycans
  • Organogenesis
  • Myocytes, Cardiac
  • Mice
  • Hyaluronic Acid
  • Humans
  • Heart