TY - JOUR
T1 - Hepatic stellate cells as key target in liver fibrosis
AU - Higashi, Takaaki
AU - Friedman, Scott L.
AU - Hoshida, Yujin
N1 - Funding Information:
This work is supported by Japan Society for the Promotion of Science , program for advancing strategic international networks to accelerate the circulation of talented researchers (to T.H.), NIH/NIDDK DK099558 , European Union ERC-2014-AdG-671231HEPCIR , Irma T. Hirschl Trust , and US Department of Defense W81XWH-16-1-0363 (to Y.H.). Some cell and organelle images in the figures are from Togo picture gallery, Database Center for Life Science (DBCLS) (licensed under creative commons 4.0).
Funding Information:
This work is supported by Japan Society for the Promotion of Science, program for advancing strategic international networks to accelerate the circulation of talented researchers (to T.H.), NIH/NIDDK DK099558, European Union ERC-2014-AdG-671231HEPCIR, Irma T. Hirschl Trust, and US Department of Defense W81XWH-16-1-0363 (to Y.H.). Some cell and organelle images in the figures are from Togo picture gallery, Database Center for Life Science (DBCLS) (licensed under creative commons 4.0).
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.
AB - Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.
KW - Alcoholic liver disease
KW - Cirrhosis
KW - Hepatitis
KW - Myofibroblast
KW - Non-alcoholic fatty liver disease
KW - Non-alcoholic steatohepatitis
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U2 - 10.1016/j.addr.2017.05.007
DO - 10.1016/j.addr.2017.05.007
M3 - Review article
C2 - 28506744
AN - SCOPUS:85019375083
SN - 0169-409X
VL - 121
SP - 27
EP - 42
JO - Advanced Drug Delivery Reviews
JF - Advanced Drug Delivery Reviews
ER -