Heparan sulfate proteoglycans mediate interstitial flow mechanotransduction regulating MMP-13 expression and cell motility via FAK-ERK in 3D collagen |
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Authors: | Shi Zhong-Dong Wang Hui Tarbell John M |
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Institution: | Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, New York, United States of America. |
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Abstract: | BackgroundInterstitial flow directly affects cells that reside in tissues and regulates
tissue physiology and pathology by modulating important cellular processes
including proliferation, differentiation, and migration. However, the structures
that cells utilize to sense interstitial flow in a 3-dimensional (3D) environment
have not yet been elucidated. Previously, we have shown that interstitial
flow upregulates matrix metalloproteinase (MMP) expression in rat vascular
smooth muscle cells (SMCs) and fibroblasts/myofibroblasts via activation of
an ERK1/2-c-Jun pathway, which in turn promotes cell migration in collagen.
Herein, we focused on uncovering the flow-induced mechanotransduction mechanism
in 3D.Methodology/Principal FindingsCleavage of rat vascular SMC surface glycocalyx heparan sulfate (HS) chains
from proteoglycan (PG) core proteins by heparinase or disruption of HS biosynthesis
by silencing N-deacetylase/N-sulfotransferase
1 (NDST1) suppressed interstitial flow-induced ERK1/2 activation, interstitial
collagenase (MMP-13) expression, and SMC motility in 3D collagen. Inhibition
or knockdown of focal adhesion kinase (FAK) also attenuated or blocked flow-induced
ERK1/2 activation, MMP-13 expression, and cell motility. Interstitial flow
induced FAK phosphorylation at Tyr925, and this activation was blocked when
heparan sulfate proteoglycans (HSPGs) were disrupted. These data suggest that
HSPGs mediate interstitial flow-induced mechanotransduction through FAK-ERK.
In addition, we show that integrins are crucial for mechanotransduction through
HSPGs as they mediate cell spreading and maintain cytoskeletal rigidity.Conclusions/SignificanceWe propose a conceptual mechanotransduction model wherein cell surface
glycocalyx HSPGs, in the presence of integrin-mediated cell-matrix adhesions
and cytoskeleton organization, sense interstitial flow and activate the FAK-ERK
signaling axis, leading to upregulation of MMP expression and cell motility
in 3D. This is the first study to describe a flow-induced mechanotransduction
mechanism via HSPG-mediated FAK activation in 3D. This study will be of interest
in understanding the flow-related mechanobiology in vascular lesion formation,
tissue morphogenesis, cancer cell metastasis, and stem cell differentiation
in 3D, and also has implications in tissue engineering. |
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