Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction.
Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction.
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DOI：
10.1038/srep26113
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发表时间：
2016-05-18
影响因子：
4.6
通讯作者：
Koizumi N
中科院分区：
文献类型：
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作者：
Okumura N;Sakamoto Y;Fujii K;Kitano J;Nakano S;Tsujimoto Y;Nakamura S;Ueno M;Hagiya M;Hamuro J;Matsuyama A;Suzuki S;Shiina T;Kinoshita S;Koizumi N
角膜内皮细胞维持角膜的透明性，因此，其功能障碍会导致严重的视力丧失。基于组织工程学的治疗作为传统供体角膜移植的替代方法，有望提供一种侵入性更小、更有效的治疗方式。我们在灵长类动物模型中进行了一项基于细胞治疗的临床前研究，证实了将培养的猴子角膜内皮细胞(MCECs)或人角膜内皮细胞(HCECs)与Rho激酶(ROCK)抑制剂Y-27632相结合注入前房后，角膜内皮再生。我们还评估了良好制造规范(GMP)级的HCECs的安全性和有效性，类似于临床试验中计划用作人类患者移植材料的HCECs，我们显示角膜内皮再生没有不良反应。我们还发现，CEC的植入受到底物黏附限制的影响，这是由于解离诱导激活ROCK/MLC信号而导致肌球蛋白收缩所致。加入ROCK抑制剂可提高CECs的植入效率，并使以细胞为基础的治疗作为临床相关治疗角膜内皮功能障碍成为可能。
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.