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Sci Rep. 2014 Sep 19;4:6425. doi: 10.1038/srep06425.

Mechanosensitive kinases regulate stiffness-induced cardiomyocyte maturation.

Author information

1
Department of Bioengineering, University of California, San Diego, CA 92093.
2
Department of Material Science Program, University of California, San Diego, CA 92093.
3
Department of Pharmacology, University of California, San Diego, CA 92093.
4
1] Department of Bioengineering, University of California, San Diego, CA 92093 [2] Department of Material Science Program, University of California, San Diego, CA 92093 [3] Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.

Abstract

Cells secrete and assemble extracellular matrix throughout development, giving rise to time-dependent, tissue-specific stiffness. Mimicking myocardial matrix stiffening, i.e. ~10-fold increase over 1 week, with a hydrogel system enhances myofibrillar organization of embryonic cardiomyocytes compared to static hydrogels, and thus we sought to identify specific mechanosensitive proteins involved. Expression and/or phosphorylation state of 309 unique protein kinases were examined in embryonic cardiomyocytes plated on either dynamically stiffening or static mature myocardial stiffness hydrogels. Gene ontology analysis of these kinases identified cardiogenic pathways that exhibited time-dependent up-regulation on dynamic versus static matrices, including PI3K/AKT and p38 MAPK, while GSK3β, a known antagonist of cardiomyocyte maturation, was down-regulated. Additionally, inhibiting GSK3β on static matrices improved spontaneous contraction and myofibril organization, while inhibiting agonist AKT on dynamic matrices reduced myofibril organization and spontaneous contraction, confirming its role in mechanically-driven maturation. Together, these data indicate that mechanically-driven maturation is at least partially achieved via active mechanosensing at focal adhesions, affecting expression and phosphorylation of a variety of protein kinases important to cardiomyogenesis.

PMID:
25236849
PMCID:
PMC4168277
DOI:
10.1038/srep06425
[Indexed for MEDLINE]
Free PMC Article
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