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Type: Journal article
Title: Effect of flightless I expression on epidermal stem cell niche during wound repair
Author: Yang, G.N.
Strudwick, X.L.
Bonder, C.
Kopecki, Z.
Cowin, A.J.
Citation: Advances in Wound Care, 2020; 9(4):161-173
Publisher: Mary Ann Liebert
Issue Date: 2020
ISSN: 2162-1918
Statement of
Gink N. Yang, Xanthe L. Strudwick, Claudine Bonder, Zlatko Kopecki, and Allison J. Cowin
Abstract: Objective: Activation of epidermal stem cells (EpSCs) from their quiescent niche is an integral component of wound reepithelialization and involves Wnt/bcatenin (b-Cat) signaling and remodeling of the actin cytoskeleton. The aim of this study was to investigate the effect of Flightless I (Flii), a cytoskeletal protein and inhibitor of wound healing, on EpSC activation during wound repair. Approach: Genetically modified Flii mice (Flii knockdown: Flii+/-, wild type: WT, Flii overexpressing: FliiTg/Tg) received two incisional wounds along the lateral axis of the dorsal skin. Indicators of EpSC activation (epidermal growth factor receptor 1 [EGFR1], leucine-rich repeats and immunoglobulin-like domains-1 [Lrig1], K14), Wnt/b-Cat signaling (Lgr6, Flap2, b-Cat, and axis inhibition protein 2 [Axin2]), and cell proliferation (proliferating cell nuclear antigen [PCNA]) were assessed using immunohistochemistry. b-Cat stabilization was examined using western blotting with cell cycling and differentiation of isolated CD34+ITGA6high EpSCs examined using real time-quantitative polymerase chain reaction after treatment with wound-conditioned media. Results: Flii+/- led to increased numbers of activated EpSCs expressing PCNA, elevated EGFR1, and decreased Lrig1. EpSCs in Flii+/- hair follicle niches adjacent to the wounds also showed expression of Wnt-activation markers including increased b-Cat and Lgr6, and decreased Axin2. EpSCs (CD34+ITGA6high) isolated from Flii+/- unwounded skin showed elevated expression of cell-cycling genes including DNp63, filaggrin (Fila), involucrin (Invo), cyclin D1 (Ccnd1), and cell-division cycle protein-20 (Cdc20); and elevated DNp63 and Invo after treatment with wound-conditioned media compared with WT and FliiTg/Tg counterparts. Innovation: Flii was identified as an inhibitor of EpSC activation that may explain its negative effects on wound reepithelialization. Conclusion: Flii may inhibit EpSC activation by interrupting Wnt/b-Cat signaling. Strategies that reduce Flii may increase activation of EpSCs and promote reepithelialization of wounds.
Keywords: Wound repair; skin; stem cells; epidermis
Description: Published Online Ahead of Print:July 3, 2019
Rights: © 2019 by Mary Ann Liebert, Inc., publishers.
DOI: 10.1089/wound.2018.0884
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