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Abstract
The migration and reepithelization of epidermal stem cells (ESCs) are the most critical processes in wound healing. The gaseous messenger nitric oxide (NO) has multiple biological effects, but its actions on ESCs are poorly understood. In this study, an NO donor, S-nitroso-N-acetylpenicillamine (SNAP), was found to facilitate the in vitro migration of human ESCs (huESCs) in both live-imaging and scratch models. In addition, pull-down assays demonstrated that SNAP could activate the small GTPases RhoA and Rac1 of the Rho family, but not Cdc42. Moreover, the effects of SNAP on the migration and F-actin polymerization of ESCs could be blocked by inhibitors of cGMP, PKG, RhoA or Rac1, and by a specific siRNA of RhoA or Rac1, but not by a Cdc42 inhibitor or siRNA. Furthermore, the roles of NO in ESC migration via cGMP-Rho GTPase signalling in vivo were confirmed by tracing 5-bromo-2-deoxyuridine (BrdU)-labelled cells in a superficial, partial-thickness scald mouse model. Thus, the present study demonstrated that the NO donor SNAP could promote huESC migration in vitro. Furthermore, NO was found to induce ESC migration via cGMP-Rho GTPase RhoA and Rac1 signalling, but not Cdc42 signalling, both in vivo and in vitro.
Highlights
Wound healing is a complex process mediated by a variety of factors responsible for the regeneration and reorganization of damaged tissue into its normal architecture
Basal keratinocytes with the cell surface phenotypes α6bri and CD71dim exhibit many predicted characteristics of huESCs26
The clonogenic capacity and expression of epidermal stem cells (ESCs) specific markers indicated that the prepared cells were ESCs
Summary
Wound healing is a complex process mediated by a variety of factors responsible for the regeneration and reorganization of damaged tissue into its normal architecture. The mechanisms of skin repair have not been completely elucidated, many cellular components are known to contribute to the maintenance of skin homeostasis and regeneration[1,2]. NO plays a critical role in wound healing by promoting cell migration and proliferation. The mechanism of NO on wound healing has been studied by several authors, but its exact signalling is not completely elucidated[12,13]. Small GTP-binding proteins of the Rho family, including RhoA, Rac[1], and Cdc[42], closely regulate actin-based structure formation and subsequentially cell migration[20,21]. We hypothesized that NO may stimulate ESC migration via cGMP-Rho GTPase signal transduction. The present study elucidated the potential effects of NO on ESC migration and identified the underlying mechanisms in vitro. Our founding might richen the mechanism of NO in wound healing
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