Extracellular component hyaluronic acid and its receptor Hmmr are required for epicardial EMT during heart regeneration

Cardiovasc Res. 2015 Sep 1;107(4):487-98. doi: 10.1093/cvr/cvv190. Epub 2015 Jul 7.


Aims: After injury, the adult zebrafish can regenerate the heart. This requires the activation of the endocardium and epicardium as well as the proliferation of pre-existing cardiomyocytes to replace the lost tissue. However, the molecular mechanisms involved in this process are not completely resolved. In this work, we aim to identify the proteins involved in zebrafish heart regeneration and to explore their function.

Methods and results: Using a proteomic approach, we identified Hyaluronan-mediated motility receptor (Hmmr), a hyaluronic acid (HA) receptor, to be expressed following ventricular resection in zebrafish. Moreover, enzymes that produce HA, hyaluronic acid synthases (has), were also expressed following injury, suggesting that this pathway may serve important functions in the regenerating heart. Indeed, suppression of HA production, as well as depletion of Hmmr, blocked cardiac regeneration. Mechanistically, HA and Hmmr are required for epicardial cell epithelial-mesenchymal transition (EMT) and their subsequent migration into the regenerating ventricle. Furthermore, chemical inhibition of Focal Adhesion Kinase (FAK) or inhibition of Src kinases, downstream effectors of Hmmr, also prevented epicardial cell migration, implicating a HA/Hmmr/FAK/Src pathway in this process. In a rat model of myocardial infarction, both HA and HMMR were up-regulated and localized in the infarct area within the first few days following damage, suggesting that this pathway may also play an important role in cardiac repair in mammals.

Conclusion: HA and Hmmr are required for activated epicardial cell EMT and migration involving the FAK/Src pathway for proper heart regeneration.

Keywords: Epicardial cell migration; Hmmr; Hyaluronic acid; Zebrafish heart regeneration; pFAK.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Adhesion / genetics
  • Cell Movement / physiology
  • Epithelial-Mesenchymal Transition / physiology*
  • Extracellular Matrix Proteins / metabolism*
  • Extracellular Space / metabolism
  • Heart / growth & development*
  • Hyaluronan Receptors / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Proteomics / methods
  • Regeneration / physiology*
  • Zebrafish / genetics
  • Zebrafish / growth & development
  • Zebrafish / metabolism*


  • Extracellular Matrix Proteins
  • Hyaluronan Receptors
  • hyaluronan-mediated motility receptor