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Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
Published on: July 10, 2019
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The non-selective Rho-kinase inhibitors Y-27632 and Y-33075 decrease contraction but increase migration in murine and
Nadine Bachtler1, Sandra Torres1, Cristina Ortiz1
1Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany.
Plos One
|January 31, 2023
Summary
Rho-kinase (ROCK) inhibitors Y-27632 and Y-33075 reduced hepatic stellate cell (HSC) contraction and proliferation. Y-33075 was more potent, but both ROCK inhibitors unexpectedly increased HSC migration.
Area of Science:
- Hepatology
- Cell Biology
- Pharmacology
Background:
- Rho-kinase (ROCK) II is crucial for hepatic stellate cell (HSC) activation, a key process in chronic liver disease.
- ROCK II inhibition blocks myosin light chain phosphorylation, reducing stress fiber assembly and cell contraction.
Purpose of the Study:
- To investigate the effects of ROCK inhibitors Y-33075 and Y-27632 on murine and human HSCs.
- To evaluate the impact of ROCK inhibition on HSC contraction, fibrogenesis, proliferation, and migration.
Main Methods:
- Primary mouse and human HSCs were treated with Y-27632 and Y-33075.
- Western blots, qPCR, wound-healing assays, BrdU assays, and 3D collagen contraction assays were employed.
- Dose-response effects (10nM to 10μM) were analyzed over 24 hours.
Main Results:
- Both Y-27632 and Y-33075 significantly reduced HSC contraction, fibrogenesis, and proliferation.
- Y-33075 exhibited 10-fold greater potency than Y-27632 in inhibiting contraction.
- A significant, unexpected increase in HSC migration was observed with both inhibitors.
Conclusions:
- ROCK inhibition effectively decreases HSC contraction and proliferation.
- Y-33075 is a more potent ROCK inhibitor for HSC contraction than Y-27632.
- Further evaluation of Y-33075 in chronic liver disease models is warranted, considering its dual effect on contraction and migration.
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