Ccn2a is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish

Development. 2021 Jan 18;148(2):dev193219. doi: 10.1242/dev.193219.


The ability of zebrafish to heal their heart after injury makes them an attractive model for investigating the mechanisms governing the regenerative process. In this study, we show that the gene cellular communication network factor 2a (ccn2a), previously known as ctgfa, is induced in endocardial cells in the injured tissue and regulates CM proliferation and repopulation of the damaged tissue. We find that, whereas in wild-type animals, CMs track along the newly formed blood vessels that revascularize the injured tissue, in ccn2a mutants CM proliferation and repopulation are disrupted, despite apparently unaffected revascularization. In addition, we find that ccn2a overexpression enhances CM proliferation and improves the resolution of transient collagen deposition. Through loss- and gain-of-function as well as pharmacological approaches, we provide evidence that Ccn2a is necessary for and promotes heart regeneration by enhancing the expression of pro-regenerative extracellular matrix genes, and by inhibiting the chemokine receptor gene cxcr3.1 through a mechanism involving Tgfβ/pSmad3 signaling. Thus, Ccn2a positively modulates the innate regenerative response of the adult zebrafish heart.

Keywords: Ccn2a; Ctgf; Extracellular matrix; Heart regeneration; TGFβ; Zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism*
  • Coronary Vessels / metabolism
  • Endocardium / pathology
  • Endocardium / physiopathology
  • Extracellular Matrix / genetics
  • Gene Expression Regulation, Developmental
  • Heart / physiopathology*
  • Mutation / genetics
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phosphorylation
  • Protein Transport
  • Regeneration*
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1 / metabolism
  • Zebrafish / physiology*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Smad Proteins
  • Transforming Growth Factor beta1
  • Zebrafish Proteins
  • ccn2a protein, zebrafish
  • Connective Tissue Growth Factor