Abstract：
Rho kinase inhibitors (ROCKi) have attracted growing multidisciplinary interest, particularly in Ophthalmology where the question as to how they promote corneal endothelial healing remains unresolved. Concurrently, stem cell biology has rapidly progressed in unravelling drivers of stem cell (SC) proliferation and differentiation, where mechanical niche factors and the actin cytoskeleton are increasingly recognized as key players. There is mounting evidence from the study of the peripheral corneal endothelium that supports the likelihood of an internal limbal stem cell niche. The possibility that ROCKi stimulate the endothelial SC niche has not been addressed. Furthermore, there is currently a paucity of data that directly evaluates whether ROCKi promotes corneal endothelial healing by acting on this limbal SC niche located near the transition zone. Therefore, we performed a systematic review examining the effects ROCKi on the proliferation and differentiation of human somatic SC, to provide insight into its effects on various human SC populations. An appraisal of electronic searches of four databases identified 1 in vivo and 58 in vitro studies (36 evaluated proliferation while 53 examined differentiation). Types of SC studied included mesenchymal (n = 32), epithelial (n = 11), epidermal (n = 8), hematopoietic and other (n = 8). The ROCK 1/2 selective inhibitor Y-27632 was used in almost all studies (n = 58), while several studies evaluated ≥2 ROCKi (n = 4) including fasudil, H-1152, and KD025. ROCKi significantly influenced human somatic SC proliferation in 81% of studies (29/36) and SC differentiation in 94% of studies (50/53). The present systemic review highlights that ROCKi are influential in regulating human SC proliferation and differentiation, and provides evidence to support the hypothesis that ROCKi promotes corneal endothelial division and maintenance via acting on the inner limbal SC niche.
摘要：
Rho激酶抑制剂（ROCKi）吸引了越来越多的多学科兴趣，特别是在眼科学中，关于它们如何促进角膜内皮愈合的问题仍未解决。同时,干细胞生物学在揭示干细胞（SC）增殖和分化的驱动因素方面取得了迅速进展，机械生态位因子和肌动蛋白细胞骨架越来越被认为是关键参与者。来自周围角膜内皮的研究越来越多的证据支持内部角膜缘干细胞壁龛的可能性。ROCKi刺激内皮SC生态位的可能性尚未得到解决。此外，目前缺乏直接评估ROCKi是否通过作用于位于过渡区附近的角膜缘SC小生境来促进角膜内皮愈合的数据.因此,我们进行了系统评价，研究了ROCKi对人体细胞SC增殖和分化的影响，以深入了解其对各种人类SC种群的影响。对四个数据库的电子搜索的评估确定了1项体内研究和58项体外研究（36项评估了增殖，53项检查了分化）。研究的SC类型包括间充质（n=32），上皮（n=11），表皮（n=8），造血和其他（n=8）。ROCK1/2选择性抑制剂Y-27632几乎用于所有研究（n=58），虽然几项研究评估了≥2ROCKi（n=4），包括法舒地尔，H-1152和KD025.在81%的研究中,ROCKi显著影响人体细胞SC增殖(29/36),在94%的研究中显著影响SC分化(50/53)。本系统综述强调ROCKi在调节人SC增殖和分化方面有影响。并提供证据支持以下假设：ROCKi通过作用于内角膜缘SC生态位促进角膜内皮分裂和维持。
