Elsevier

Developmental Biology

Volume 382, Issue 2, 15 October 2013, Pages 457-469
Developmental Biology

A dynamic spatiotemporal extracellular matrix facilitates epicardial-mediated vertebrate heart regeneration

https://doi.org/10.1016/j.ydbio.2013.08.002Get rights and content
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Highlights

  • ECM remodeling is a conserved process during vertebrate heart regeneration.

  • Tenascin-C, hyaluronic acid, and fibronectin compose a regeneration-specific matrix.

  • Ventricular resection triggers a myocardium-wide proliferative response.

  • Tenascin-C supports cell cycle entry in newt cardiomyocytes.

  • Progenitor cells migrate radially to the regenerative ECM-rich epicardium and apex.

Abstract

Unlike humans, certain adult vertebrates such as newts and zebrafish possess extraordinary abilities to functionally regenerate lost appendages and injured organs, including cardiac muscle. Here, we present new evidence that a remodeled extracellular matrix (ECM) directs cell activities essential for cardiac muscle regeneration. Comprehensive mining of DNA microarrays and Gene Ontology term enrichment analyses for regenerating newt and zebrafish hearts revealed that distinct ECM components and ECM-modifying proteases are among the most significantly enriched genes in response to local injury. In contrast, data analyses for mammalian cardiac injury models indicated that inflammation and metabolic processes are the most significantly activated gene groups. In the regenerating newt heart, we show dynamic spatial and temporal changes in tenascin-C, hyaluronic acid, and fibronectin ECM distribution as early as 3 days postamputation. Linked to distinct matrix remodeling, we demonstrate a myocardium-wide proliferative response and radial migration of progenitor cells. In particular, we report dramatic upregulation of a regeneration-specific matrix in the epicardium that precedes the accumulation and migration of progenitor cells. For the first time, we show that the regenerative ECM component tenascin-C significantly increases newt cardiomyocyte cell cycle reentry in vitro. Thus, the engineering of nature-tested extracellular matrices may provide new strategic opportunities for the enhancement of regenerative responses in mammals.

Keywords

Heart
Regeneration
Extracellular matrix
Newt
Myocardial infarction

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