Event
Bioengineering Seminar Series: Shaik Rahaman
Friday, November 13, 2015
9:00 a.m.-10:00 a.m.
Pepco Room (1105), Jeong H. Kim Engineering Building
Dr. Jose Helim Aranda-Espinoza
helim@umd.edu
Shaik Rahaman
Assistant Professor
Department of Nutrition & Food Science
University of Maryland
TRPV4 mechanotransduction in cell differentiation
The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGFβ1; however, it is not clear how fibroblasts sense and transmit the mechanical signal(s) that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 (TRPV4) channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether TRPV4 contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that TRPV4 activity is upregulated in lung fibroblasts derived from patients with lung fibrosis. Moreover, TRPV4-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of TRPV4 function abrogated myofibroblast differentiation, which was restored by TRPV4 reintroduction. TRPV4 channel activity was elevated when cells were plated on matrices of increasing stiffness, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRPV4 inhibition. TRPV4 activity modulated TGFβ1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the α-SMA transcription coactivator (MRTF-A). Together, these data indicate that TRPV4 activity mediates pulmonary fibrogenesis and suggest that manipulation of TRPV4 channel activity has potential as a therapeutic approach for fibrotic diseases. The differentiation of macrophages to lipid-laden foam cells and their trapping in the intimal areas are critically important to the in vivo development and progression of atherosclerosis. It is well recognized that mechanosensing plays a critical role throughout the atherogenesis process. Recently, we have identified TRPV4 as a novel regulator of foam cell formation and macrophage migration.
