Document Detail

Substrate stiffness modulates gene expression and phenotype in neonatal cardiomyocytes in vitro.
MedLine Citation:
PMID:  22519549     Owner:  NLM     Status:  Publisher    
Biomaterials to be used as cell delivery systems for cardiac tissue engineering should be able to comply with cardiac muscle contractile activity, while favoring cell survival and neo-angiogenesis in a hostile environment. Biocompatible synthetic materials can be tailored to mimic cardiac tissue three-dimensional organization in the micro- and nanoscale. Nonetheless, they usually display mechanical properties which are far from those of the native myocardium and thus could affect host cell survival and activity. In the present investigation, inert poly--caprolactone (PCL) planar layers were manufactured to change the surface stiffness (with Young modulus ranging from 1 to 133 MPa) without changing matrix chemistry. These substrates were challenged with neonatal murine cardiomyocytes to study the possible effect of substrate stiffness on such cell behavior without changing biological cues. Interestingly, softer substrates (0.91±0.08 MPa and 1.53±0.16 MPa) were found to harbor mostly mature cardiomyocytes having assembled sarcomeres, as shown by the expression of alpha sarcomeric actinin and myosin heavy chain in typical striations and the up-regulation of sarcomeric actin mRNA. On the other hand, a preferential expression of immature cardiac cell genes (Nkx-2.5) and proteins (GATA-4) in cardiac cells grown onto stiffer materials (49.67±2.56 MPa and 133.23±8.67 MPa) was detected. This result could not be ascribed to significant differences in cell adhesion or proliferation induced by the substrates, but to the stabilization of cardiomyocyte differentiated phenotype induced by softer layers. In fact, cardiac cell electromechanical coupling was shown to be more organized on softer surfaces, as highlighted by connexin 43 distribution. Moreover, a differential regulation of genes involved in extracellular matrix remodeling was detected on soft films (0.91±0.08 MPa) as compared to the stiffest (133.23±8.67 MPa). Finally, the up-regulation of a number of genes involved in inflammatory processes was detected when the stiffest polymer is used. These events highlight the differences in cell mechanosensitivity in a heterogeneous cell preparation and are likely to contribute to the differences encountered in cardiac cell phenotype induced by substrate stiffness.
Giancarlo Forte; Stefania Pagliari; Mitsuhiro Ebara; Koichiro Uto; Janice Kal Van Tam; Sara Romanazzo; Carmen Escobedo-Lucea; Elena Romano; Paolo Di Nardo; Enrico Traversa; Takao Aoyagi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-20
Journal Detail:
Title:  Tissue engineering. Part A     Volume:  -     ISSN:  1937-335X     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101466659     Medline TA:  Tissue Eng Part A     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
National Institute for Materials Science (NIMS), International Center for Materials Nanoarchitectonics (MANA), 1-1 Namiki, Tsukuba, Japan, 305-0044, +81-29-85133548765;
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