Targeting myosin 1c inhibits murine hepatic fibrogenesis

File Description SizeFormat 
ajpgi_ March 2021 - accepted version.pdfAccepted version19.84 MBAdobe PDFView/Open
Title: Targeting myosin 1c inhibits murine hepatic fibrogenesis
Authors: Arif, E
Wang, C
Swiderska-Syn, MK
Solanki, AK
Rahman, B
Manka, PP
Coombes, J
Canbay, A
Papa, S
Nihalani, D
Lipschutz, JH
Syn, W-K
Item Type: Journal Article
Abstract: Myosin 1c (Myo1c) is an unconventional myosin that modulates signaling pathways involved in tissue injury and repair. In this study, we observed that Myo1c expression is significantly upregulated in human chronic liver disease such as nonalcoholic steatohepatitis (NASH) and in animal models of liver fibrosis. High throughput data from the GEO-database identified similar Myo1c upregulation in mice and human liver fibrosis. Notably, TGF-β stimulation to hepatic stellate cells (HSCs, the liver pericyte and key cell type responsible for the deposition of extracellular matrix upregulates Myo1c expression, while genetic depletion or pharmacological inhibition of Myo1c blunted TGF-β induced fibrogenic responses, resulting in repression of α-SMA and Col1α1 mRNA. Myo1c deletion also decreased fibrogenic processes such as cell proliferation, wound healing response and contractility when compared with vehicle treated HSCs. Importantly, phosphorylation of SMAD2 and SMAD3 were significantly blunted upon Myo1c inhibition in GRX cells as well as Myo1c-KO MEFs upon TGF-β stimulation. Using the genetic Myo1c knockout (Myo1c-KO) mice, we confirmed that Myo1c is critical for fibrogenesis as Myo1c-KO mice were resistant to CCl4 induced liver fibrosis. Histological and immunostaining analysis of liver sections showed that deposition of collagen fibers and α-SMA expression were significantly reduced in Myo1c-KO mice upon liver injury. Collectively, these results demonstrate that Myo1c-mediates hepatic fibrogenesis by modulating TGF-β signaling and suggest that inhibiting this process may have clinical application in treating liver fibrosis.
Issue Date: 1-Jun-2021
Date of Acceptance: 28-Apr-2021
URI: http://hdl.handle.net/10044/1/89695
DOI: 10.1152/ajpgi.00105.2021
ISSN: 0193-1857
Publisher: American Physiological Society
Start Page: G1044
End Page: G105
Journal / Book Title: American Journal of Physiology: Gastrointestinal and Liver Physiology
Volume: 320
Issue: 6
Copyright Statement: © 2021 Published by the American Physiological Society.
Keywords: Myo1c
TGF-β signaling
hepatic fibrosis
Hepatic Stellate Cells
Hepatic fibrosis
Myo1c
TGF-β signaling
Gastroenterology & Hepatology
0606 Physiology
1116 Medical Physiology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2021-06-14
Appears in Collections:Department of Metabolism, Digestion and Reproduction