A ROCK Inhibitor Promotes Graft Survival during Transplantation of iPS-Cell-Derived Retinal Cells

Abstract

Currently, retinal pigment epithelium (RPE) transplantation includes sheet and single-cell transplantation, the latter of which includes cell death and may be highly immunogenic, and there are some issues to be improved in single-cell transplantation. Y-27632 is an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of Rho. We herein investigated the effect of Y-27632 in vitro on retinal pigment epithelium derived from induced pluripotent stem cells (iPS-RPE cells), and also its effects in vivo on the transplantation of iPS-RPE cell suspensions. As a result, the addition of Y-27632 in vitro showed suppression of apoptosis, promotion of cell adhesion, and higher proliferation and pigmentation of iPS-RPE cells. Y-27632 also increased the viability of the transplant without showing obvious retinal toxicity in human iPS-RPE transplantation into monkey subretinal space in vivo. Therefore, it is possible that ROCK inhibitors can improve the engraftment of iPS-RPE cell suspensions after transplantation.

A Rho Kinase (ROCK) Inhibitor, Y-27632, Inhibits the Dissociation-Induced Cell Death of Salivary Gland Stem Cells

“…Salivary gland epithelial cell-derived spheroids cultured with Y-27632 increased the expression levels of the salivary gland stem cell marker c-Kit [ 10 ], and the transplantation of c-Kit-positive cells restored the tissue homeostasis in an irradiated salivary gland [ 11 ]. In addition, the survival of induced pluripotent cell-derived retinal cells transplanted into subretinal space was promoted by Y-27632 [ 47 ]. In this study, Y-27632 promoted not only the survival but also the differentiation of SGSCs.…”

Current Development, Obstacle and Futural Direction of Induced Pluripotent Stem Cell and Mesenchymal Stem Cell Treatment in Degenerative Retinal Disease

“…Effort has been devoted to promoting the survival of grafted cells. Rho-associated protein kinase (ROCK) inhibitor was found to promote iPSC retinal cell survival and cell adhesion in vitro, and no toxic effect was noted in a monkey model [ 68 ]. We need longer observation periods to evaluate the lifespan of grafted cells in general as we expect that iPSC therapy can slow disease progression and improve vision; however, a rescue algorithm might need to be established to deal with graft tissue failure.…”

Recent Progress in Retinal Pigment Epithelium Cell-Based Therapy for Retinal Disease

“…In this context, it is noteworthy that Croze et al 74 reported that Rho associated kinase (ROCK) inhibition promotes attachment, proliferation, and wound closure of human ESC-RPE in cell culture. These authors suggested that pharmacological approaches such as this one might even be used to stimulate in situ RPE to resurface areas of AMD-GA. Ishida et al 75 studied the effects of the pan-ROCK inhibitor, Y-27632, on iPSC-RPE in vitro and in vivo. In vitro, these investigators found that ROCK inhibition promoted proliferation and cell-cell and cell-substrate adhesion in human iPSC-RPE.…”