Abstract Book Cover - Weinstein 2012 - University of Chicago

S2.6 A Transitional Extracellular Matrix Instructs Epicardial-mediated Vertebrate Heart Regeneration
Sarah Mercer 1 , Claudia Guzman 1 , Chia-ho Cheng 2 , Shannon Odelberg 3 , Ken Marx 2 and Hans-Georg Simon 1
1
Department of Pediatrics and Children’s Memorial Research Center, Northwestern University Feinberg School
of Medicine, Chicago IL, USA
2
Department of Chemistry, University of Massachusetts-Lowell, USA
3
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City UT, USA
Unlike humans, certain vertebrates including newts and zebrafish possess extraordinary abilities to functionally
regenerate lost appendages and injured organs, including cardiac muscle. We aim to discover the underpinning
mechanisms that regulate complex tissue rebuilding in these regeneration-competent species, ultimately
developing strategies for regenerative wound healing in mammals. Here, we present new evidence that the
extracellular matrix (ECM) provides signals to tissues and cells essential for the induction and maintenance of
regenerative processes in cardiac muscle. Comprehensive mining of DNA microarrays of regenerating newt and
zebrafish hearts with data comparison to the scar-forming response following myocardial infarction in mice and
humans provided a signature of conserved regenerative gene activities. Differential expression and Gene
Ontology analyses revealed that distinct ECM components and ECM-modifying proteases are among the
earliest upregulated and most significantly enriched genes in response to injury in both the newt and zebrafish.
In contrast, following mammalian cardiac injury, immune and inflammatory responses are significantly activated
instead of ECM genes. Complementary immunohistochemistry studies in the newt demonstrated dynamic
spatial and temporal changes in ECM composition between normal and regenerating heart tissues, especially in
the epicardium early in the regenerative response. We show in vivo and under defined culture conditions that
the proliferative and migratory response of cardiomyocytes is directly linked to distinct matrix remodeling in both
the myocardium and epicardium of the regenerating newt heart. Collectively, these results provide a novel
understanding of the regenerative process, suggesting that an evolutionarily conserved, regeneration-specific
matrix instructs cell activities essential for cardiac muscle regeneration.
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