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

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.

The extracellular matrix in myocardial injury, repair, and remodeling

“…In newts, cardiac regeneration following injury was preceded by formation of a matrix network comprising tenascin-C, fibronectin, and hyaluronan. This specialized matrix network may serve as a path for progenitor cells as well as play an active role in activation of a regenerative program (145). Considering that, much like in fish and amphibians, myocardial infarction in mammals also induces a marked upregulation of tenascin-C and fibronectin without stimulating remuscularization, it is unlikely that matrix-dependent actions are sufficient to activate a regenerative program.…”

Development of a human cardiac organoid injury model reveals innate regenerative potential

“…These regenerative animals initially deposit extracellular matrix (ECM) proteins, similar to the response of the mammalian heart following injury; but, in contrast, the scar tissue is degraded and replaced by proliferating cardiomyocytes (Chablais et al, 2011;Mercer et al, 2013;Poss et al, 2002). Recently, this regenerative capacity has been shown to exist in a mammalian system.…”

Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

“…After injury, a dramatic change in the composition of the ECM occurs, providing mechanical support to the injured tissue and directly modulating the inflammatory and reparative responses. [24][25][26] Recently, an ECM-targeting drug delivery strategy has been used to treat glioma 27 and enhance tissue healing. 28 However, to the best of our knowledge, little has been done to understand the feasibility of ECM as a therapeutic target for heart repair.…”