Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction

Naoki Okumura, Yuji Sakamoto, Keita Fujii, Junji Kitano, Shinichiro Nakano, Yuki Tsujimoto, Shin Ichiro Nakamura, Morio Ueno, Michio Hagiya, Junji Hamuro, Akifumi Matsuyama, Shingo Suzuki, Takashi Shiina, Shigeru Kinoshita, Noriko Koizumi

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The corneal endothelium maintains corneal transparency; consequently, its dysfunction causes severe vision loss. Tissue engineering-based therapy, as an alternative to conventional donor corneal transplantation, is anticipated to provide a less invasive and more effective therapeutic modality. We conducted a preclinical study for cell-based therapy in a primate model and demonstrated regeneration of the corneal endothelium following injection of cultured monkey corneal endothelial cells (MCECs) or human CECs (HCECs), in combination with a Rho kinase (ROCK) inhibitor, Y-27632, into the anterior chamber. We also evaluated the safety and efficacy of Good Manufacturing Practice (GMP)-grade HCECs, similar to those planned for use as transplant material for human patients in a clinical trial, and we showed that the corneal endothelium was regenerated without adverse effect. We also showed that CEC engraftment is impaired by limited substrate adhesion, which is due to actomyosin contraction induced by dissociation-induced activation of ROCK/MLC signaling. Inclusion of a ROCK inhibitor improves efficiency of engraftment of CECs and enables cell-based therapy for treating corneal endothelial dysfunction as a clinically relevant therapy.

Original languageEnglish
Article number26113
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 18-05-2016

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Corneal Endothelium
rho-Associated Kinases
Cell- and Tissue-Based Therapy
Actomyosin
Corneal Transplantation
Anterior Chamber
Tissue Engineering
Complementary Therapies
Primates
Haplorhini
Regeneration
Endothelial Cells
Tissue Donors
Clinical Trials
Transplants
Safety
Injections
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Cite this

Okumura, N., Sakamoto, Y., Fujii, K., Kitano, J., Nakano, S., Tsujimoto, Y., ... Koizumi, N. (2016). Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. Scientific reports, 6, [26113]. https://doi.org/10.1038/srep26113
Okumura, Naoki ; Sakamoto, Yuji ; Fujii, Keita ; Kitano, Junji ; Nakano, Shinichiro ; Tsujimoto, Yuki ; Nakamura, Shin Ichiro ; Ueno, Morio ; Hagiya, Michio ; Hamuro, Junji ; Matsuyama, Akifumi ; Suzuki, Shingo ; Shiina, Takashi ; Kinoshita, Shigeru ; Koizumi, Noriko. / Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. In: Scientific reports. 2016 ; Vol. 6.
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Okumura, N, Sakamoto, Y, Fujii, K, Kitano, J, Nakano, S, Tsujimoto, Y, Nakamura, SI, Ueno, M, Hagiya, M, Hamuro, J, Matsuyama, A, Suzuki, S, Shiina, T, Kinoshita, S & Koizumi, N 2016, 'Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction', Scientific reports, vol. 6, 26113. https://doi.org/10.1038/srep26113

Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. / Okumura, Naoki; Sakamoto, Yuji; Fujii, Keita; Kitano, Junji; Nakano, Shinichiro; Tsujimoto, Yuki; Nakamura, Shin Ichiro; Ueno, Morio; Hagiya, Michio; Hamuro, Junji; Matsuyama, Akifumi; Suzuki, Shingo; Shiina, Takashi; Kinoshita, Shigeru; Koizumi, Noriko.

In: Scientific reports, Vol. 6, 26113, 18.05.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction

AU - Okumura, Naoki

AU - Sakamoto, Yuji

AU - Fujii, Keita

AU - Kitano, Junji

AU - Nakano, Shinichiro

AU - Tsujimoto, Yuki

AU - Nakamura, Shin Ichiro

AU - Ueno, Morio

AU - Hagiya, Michio

AU - Hamuro, Junji

AU - Matsuyama, Akifumi

AU - Suzuki, Shingo

AU - Shiina, Takashi

AU - Kinoshita, Shigeru

AU - Koizumi, Noriko

PY - 2016/5/18

Y1 - 2016/5/18

N2 - The corneal endothelium maintains corneal transparency; consequently, its dysfunction causes severe vision loss. Tissue engineering-based therapy, as an alternative to conventional donor corneal transplantation, is anticipated to provide a less invasive and more effective therapeutic modality. We conducted a preclinical study for cell-based therapy in a primate model and demonstrated regeneration of the corneal endothelium following injection of cultured monkey corneal endothelial cells (MCECs) or human CECs (HCECs), in combination with a Rho kinase (ROCK) inhibitor, Y-27632, into the anterior chamber. We also evaluated the safety and efficacy of Good Manufacturing Practice (GMP)-grade HCECs, similar to those planned for use as transplant material for human patients in a clinical trial, and we showed that the corneal endothelium was regenerated without adverse effect. We also showed that CEC engraftment is impaired by limited substrate adhesion, which is due to actomyosin contraction induced by dissociation-induced activation of ROCK/MLC signaling. Inclusion of a ROCK inhibitor improves efficiency of engraftment of CECs and enables cell-based therapy for treating corneal endothelial dysfunction as a clinically relevant therapy.

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Okumura N, Sakamoto Y, Fujii K, Kitano J, Nakano S, Tsujimoto Y et al. Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. Scientific reports. 2016 May 18;6. 26113. https://doi.org/10.1038/srep26113