Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell-derived neural precursors
Article first published online: 7 SEP 2007
Copyright © 2007 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 86, Issue 2, pages 270–280, 1 February 2008
How to Cite
Koyanagi, M., Takahashi, J., Arakawa, Y., Doi, D., Fukuda, H., Hayashi, H., Narumiya, S. and Hashimoto, N. (2008), Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell-derived neural precursors. J. Neurosci. Res., 86: 270–280. doi: 10.1002/jnr.21502
- Issue published online: 8 JAN 2008
- Article first published online: 7 SEP 2007
- Manuscript Accepted: 15 JUL 2007
- Manuscript Revised: 11 JUN 2007
- Manuscript Received: 28 MAR 2007
- Kobe Cluster and Establishment of International COE for Integration of Transplantation Therapy and Regenerative Medicine from the MEXT of Japan
- Society of Catecholamine and Nervous Disease
- embryonic stem cells;
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.