Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell‐derived neural precursors
Open accessAbstract
Rho‐GTPase has been implicated in the apoptosis of many cell types, including neurons, but the mechanism by which it acts is not fully understood. Here, we investigate the roles of Rho and ROCK in apoptosis during transplantation of embryonic stem cell‐derived neural precursor cells. We find that dissociation of neural precursors activates Rho and induces apoptosis. Treatment with the Rho inhibitor C3 exoenzyme and/or the ROCK inhibitor Y‐27632 decreases the amount of dissociation‐induced apoptosis (anoikis) by 20–30%. Membrane blebbing, which is an early morphological sign of apoptosis; cleavage of caspase‐3; and release of cytochrome c from the mitochondria are also reduced by ROCK inhibition. These results suggest that dissociation of neural precursor cells elicits an intrinsic pathway of cell death that is at least partially mediated through the Rho/ROCK pathway. Moreover, in an animal transplantation model, inhibition of Rho and/or ROCK suppresses acute apoptosis of grafted cells. After transplantation, tumor necrosis factor‐α and pro‐nerve growth factor are strongly expressed around the graft. ROCK inhibition also suppresses apoptosis enhanced by these inflammatory cytokines. Taken together, these results indicate that inhibition of Rho/ROCK signaling may improve survival of grafted cells in cell replacement therapy. © 2007 Wiley‐Liss, Inc.
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RhoA signalling might potentially contribute to cell death, because it can promote apoptosis in low-adhesion environments by increasing cell contractility.
“RhoA signalling might also potentially contribute to cell death, because it can promote apoptosis in low-adhesion environments by increasing cell contractility, explaining why ROCK inhibitors are a standard component of media for stem cells and organoid isolation and maintenance in culture 77-81 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [79]
The paper summary (page not specified) reports that dispersing mouse embryonic stem cell–derived neural precursors activated Rho and led to cell death, which Rho and ROCK inhibitors reduced. The examination summary likewise links loss of cell adhesion to Rho/ROCK activity and apoptosis. Neither passage establishes increased cell contractility as the mechanism, or says ROCK inhibitors are standard components of stem-cell and organoid culture media. (LLM, conf=0.84)
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References 71 · Cited by 152
- Authors
- Koyanagi, M., Takahashi, J., Arakawa, Y., Doi, D., Fukuda, H., Hayashi, H., Narumiya, S., & Hashimoto, N.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Takahashi, Jun
- ORCID
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2007-09-07
- Volume
- 86
- Issue
- 2
- Pages
- 270-280
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2095013780
- Cited by
- 152
- References
- 71
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 5 · 2016: 12 · 2015: 7 · 2014: 11 · 2013: 16 · 2012: 9
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Rho/ROCK signaling, apoptosis, anoikis, C3 exoenzyme, Y-27632, caspase-3, cytochrome c release, membrane blebbing, TNF-α, nerve growth factor, graft survival, cell replacement therapy, Rho GTPases
- MeSH terms
- Animals, Flow Cytometry, Fluorescent Antibody Technique, Male, Mice, Inbred C57BL, Neurons, Blotting, Western, Signal Transduction, Apoptosis, In Situ Nick-End Labeling, rho GTP-Binding Proteins, Stem Cell Transplantation, Mice, Embryonic Stem Cells
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