A systematic review on the effects of ROCK inhibitors on proliferation and/or differentiation in human somatic stem cells: A hypothesis that ROCK inhibitors support corneal endothelial healing via acting on the limbal stem cell niche

In recent years, there has been growing interest regarding the promotion of corneal endothelial (CE) healing by rho kinase (ROCK) inhibitors. Concurrently, stem cell (SC) biology has rapidly progressed in unraveling the drivers of stem cell proliferation and differentiation, with mechanical niche factors and the actin cytoskeleton being increasingly recognized as key players, together with soluble factors. As such, ROCK inhibitors (ROCKi) are influential in modulating SC self-renewal and fate commitments (reviewed elsewhere [1]) via their action on the actin cytoskeleton, together with non-canonical targets of ROCKi which may also play a role.

Accumulating evidence from studies of the peripheral CE support the existence of an internal limbal niche located at the transition zone, which houses a reservoir of stem/progenitor-like corneal endothelial cells (CECs), described by Yu et al. as “progenitor cells of the endothelium and trabeculum” (PET) [2,3]. It is well known from clinical studies that a pool of healthy CECs in the periphery of the cornea is needed for wound healing, potentially accomplished by this PET reservoir. However, the possibility that ROCKi stimulate the PET niche has not been addressed, and currently there is insufficient accumulated data to directly evaluate whether ROCKi promote CE healing by acting on SC located within the CE niche.

Consensus has not been reached in defining a marker panel specific for CECs. Importantly, the widely used CEC markers – Na+/K + ATPase (ATP1A1), ZO-1 (TJP1) and collagen type VIII (COL8) [4], – are also expressed by other cells including lung [5] and corneal epithelium [6]. Immunofluorescence also indicated small numbers of fibroblastic CECs to be present in the stroma of human foetal and adult limbal/peripheral corneas in ex vivo studies [7]. Therefore, particularly in the context of CEC regenerative medicine, some groups have proposed more extensive panels [[8], [9], [10]]. Similarly, a defined marker panel to isolate PET is lacking, although p75NTR (highly expressed in CE stem/progenitor cells) may be important to distinguish PET from primary CECs [11,12], together with stem and neural crest markers [[13], [14], [15]], retained multipotency [13,16,17], and sphere/colony forming propensity/efficacy [13]. These challenges may partially explain the lack of data directly evaluating ROCKi effects on PET proliferation, differentiation and/or migration. In view of this paucity of data, we performed a systematic review examining the effects of ROCKi on proliferation and differentiation in human somatic SC, and have extrapolated these findings to the cornea to hypothesise that ROCKi may act on the peripheral reservoir of stem/progenitor-like CECs to promote wound healing.

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