Abstract
BackgroundCOUP-TF interacting protein 2 [(Ctip2), also known as Bcl11b] is an important regulator of skin homeostasis, and is overexpressed in head and neck cancer. Ctip2ep−/− mice, selectively ablated for Ctip2 in epidermal keratinocytes, exhibited impaired terminal differentiation and delayed epidermal permeability barrier (EPB) establishment during development, similar to what was observed in Ctip2 null (Ctip2−/−) mice. Considering that as an important role of Ctip2, and the fact that molecular networks which underlie cancer progression partially overlap with those responsible for tissue remodeling, we sought to determine the role of Ctip2 during cutaneous wound healing.Methodology/Principal FindingsFull thickness excisional wound healing experiments were performed on Ctip2L2/L2 and Ctip2ep−/− animals per time point and used for harvesting samples for histology, immunohistochemistry (IHC) and immunoblotting. Results demonstrated inherent defects in proliferation and migration of Ctip2 lacking keratinocytes during re-epithelialization. Mutant mice exhibited reduced epidermal proliferation, delayed keratinocyte activation, altered cell-cell adhesion and impaired ECM development. Post wounding, Ctip2ep−/− mice wounds displayed lack of E-Cadherin suppression in the migratory tongue, insufficient expression of alpha smooth muscle actin (alpha SMA) in the dermis, and robust induction of K8. Importantly, dysregulated expression of several hair follicle (HF) stem cell markers such as K15, NFATc1, CD133, CD34 and Lrig1 was observed in mutant skin during wound repair.Conclusions/SignificanceResults confirm a cell autonomous role of keratinocytic Ctip2 to modulate cell migration, proliferation and/or differentiation, and to maintain HF stem cells during cutaneous wounding. Furthermore, Ctip2 in a non-cell autonomous manner regulated granulation tissue formation and tissue contraction during wound closure.
Highlights
Cutaneous wound healing is a highly coordinated physiological process which involves a cross-talk between different cell types such as keratinocytes, fibroblasts, and immune cells [1,2,3,4]
IHC analysis of depilation induced hair cycle revealed that mice anagen hair follicle (HF) had predominant expression of Ctip2 in the proliferative hair germ
We observed an increased epidermal thickness with a concomitant increase in Ki67- positive proliferating keratinocytes in basal and suprabasal layers but not in Ctip2 expression, suggesting that Ctip2 is linked with cell proliferation, but is not induced post TPA or Retinoic Acid (RA) treatment (Fig. S1A and B)
Summary
Cutaneous wound healing is a highly coordinated physiological process which involves a cross-talk between different cell types such as keratinocytes, fibroblasts, and immune cells [1,2,3,4]. Upon injury there is a break in EPB function, and regeneration of the epidermis post wounding involves activation, migration and proliferation of keratinocytes from surrounding epidermis and adnexal structures (HF and sweat gland) [5,6]. Re-epithelialization after epidermal injury involves resurfacing of the wound with new epithelium thereby providing rapid restoration of epidermal integrity and barrier function [7,8,9]. Migration and proliferation at the periphery of the wound are regulated by various growth factors, integrins, the extracellular matrix, and other regulatory proteins [8,12]. Considering that as an important role of Ctip, and the fact that molecular networks which underlie cancer progression partially overlap with those responsible for tissue remodeling, we sought to determine the role of Ctip during cutaneous wound healing
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