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Investigation of stretch- and stiffness-induced pro-fibrotic mechanotransduction activity in cardiac fibroblasts


Cardiac fibrosis is the excessive accumulation of extra-cellular matrix that is mainly

regulated by the activation of cardiac fibroblasts and their differentiation into myofibroblasts.

Mechanical forces are important regulators of cardiac fibroblast activation. However, it is not

clear which fibrotic signaling pathways are activated by the specific mechanical cues. Therefore,

we used in vitro stretch models as well as stiff and soft hydrogels to examine how mechanical

stretch and stiffness impacts the pathways involved in cardiac fibroblasts’ ability to generate

fibrotic phenotypes. Treatment of cardiac fibroblasts on plastic with transforming growth factor

β receptor I inhibitor resulted in lower mRNA expression levels for key myofibroblast gene

markers. Transforming growth factor β receptor I inhibitor also eliminated the stretch induced

upregulation of key fibrotic genes for fibroblasts on soft gels but only eliminated upregulation of

the smooth muscle α-actin gene on stiff gels. Surprisingly, inhibition of Rho kinase did not

impact expression levels of pro-fibrotic genes for cardiac fibroblasts on plastic and hydrogels.

Due to complications with the hydrogel stiffness, atomic force microscopy showed that

hydrogels can change their stiffness after fabrication depending on the environment the gel is in,

explaining the unusual cellular response we were experiencing with the fibroblasts on hydrogels.

Overall, transforming growth factor β signaling does significantly influence how cardiac

fibroblasts generate pro-fibrotic phenotypes. However due to the revelation of the changing

stiffness with the hydrogels, more work is needed to determine whether this pathway is more

involved in stretch responses or stiffness responses. More research is needed to determine

whether inhibiting transforming growth factor β signaling in cardiac fibroblasts can be used to

maintain a freshly isolated phenotype while culturing large quantities of cardiac fibroblasts for

longer periods on plastic tissue culture substrates.

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