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Mechanosensitive kinases regulate stiffness-induced cardiomyocyte maturation.

Jennifer L Young1, Kyle Kretchmer1, Matthew G Ondeck2

  • 1Department of Bioengineering, University of California, San Diego, CA 92093.

Scientific Reports
|September 20, 2014
PubMed
Summary

Dynamic changes in cardiac matrix stiffness guide embryonic cardiomyocyte maturation by activating specific protein kinases. This study identifies key pathways like PI3K/AKT and p38 MAPK involved in this mechanosensitive process.

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Area of Science:

  • Cardiovascular Biology
  • Biomaterials Science
  • Cellular Mechanotransduction

Background:

  • Cellular development involves dynamic extracellular matrix (ECM) stiffening, influencing tissue-specific properties.
  • Myocardial matrix stiffening, a ~10-fold increase over one week, is crucial for cardiomyocyte development.
  • Mimicking this dynamic stiffening with hydrogels enhances embryonic cardiomyocyte organization.

Purpose of the Study:

  • To identify specific mechanosensitive proteins involved in myocardial matrix stiffening-driven cardiomyocyte maturation.
  • To investigate the role of protein kinases in response to dynamic versus static matrix stiffness.
  • To elucidate the signaling pathways mediating mechanically-driven cardiomyogenesis.

Main Methods:

  • Embryonic cardiomyocytes were cultured on dynamically stiffening and static hydrogels mimicking myocardial ECM.
  • Expression and phosphorylation of 309 unique protein kinases were analyzed.
  • Gene ontology analysis and pharmacological inhibition of key kinases (GSK3β, AKT) were employed.

Main Results:

  • Dynamic matrix stiffening upregulated cardiogenic pathways, including PI3K/AKT and p38 MAPK.
  • Glycogen synthase kinase 3 beta (GSK3β), a maturation antagonist, was downregulated on dynamic matrices.
  • Inhibition of GSK3β on static matrices improved cardiomyocyte function; AKT inhibition on dynamic matrices impaired it.

Conclusions:

  • Mechanically-driven cardiomyocyte maturation is partly mediated by mechanosensing at focal adhesions.
  • Dynamic ECM stiffness influences the expression and phosphorylation of critical protein kinases.
  • Key pathways like PI3K/AKT, p38 MAPK, and GSK3β are integral to cardiomyogenesis under mechanical cues.