Modulation of sonic hedgehog-induced mouse embryonic stem cell behaviours through E-cadherin expression and integrin β1-dependent F-actin formation.

Abstract:

BACKGROUND AND PURPOSE:The sonic hedgehog pathway (Shh) plays a central role in maintaining stem cell function and behaviour in various processes related to self-renewal and tissue regeneration. However, the therapeutic effect of Shh on mouse embryonic stem cells (mESCs) has not yet been clearly elucidated. Thus, we investigated the effect of Shh on the regulation of mESC behaviour as well as the effect of Shh-pretreated mESCs in skin wound healing. EXPERIMENTAL APPROACH:The underlying mechanisms of Shh signalling pathway in growth and motility of mESCs were investigated using Western blot analysis, a cell proliferation assay and cell migration assay. In addition, the effect of Shh-pretreated mESCs in skin wound healing was determined using a mouse excisional wound splinting model. KEY RESULTS:Shh disrupted the adherens junction through proteolysis by activating MMPs. In addition, the release of β-catenin from adherens junctions mediated by Shh led to cell cycle-dependent mESC proliferation. Shh-mediated Gli1 expression led to integrin β1 up-regulation, followed by FAK and Src phosphorylation. Furthermore, among the Rho-GTPases, Rac1 and Cdc42 were activated in a Shh-dependent manner while F-actin expression was suppressed by Rac1 and Cdc42 siRNA transfection. Consistent with the in vitro results, the skin wound healing assay revealed that Shh-treated mESCs increased angiogenesis and skin wound repair compared to that in Shh-treated mESCs transfected with integrin β1 siRNA in vivo. CONCLUSIONS AND IMPLICATIONS:Our results imply that Shh induces adherens junction disruption and integrin β1-dependent F-actin formation by a mechanism involving FAK/Src and Rac1/Cdc42 signalling pathways in mESCs.

journal_name

Br J Pharmacol

authors

Oh JY,Suh HN,Choi GE,Lee HJ,Jung YH,Ko SH,Kim JS,Chae CW,Lee CK,Han HJ

doi

10.1111/bph.14423

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

3548-3562

issue

17

eissn

0007-1188

issn

1476-5381

journal_volume

175

pub_type

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