Department of Pathology, School of Medicine, University of Southern California, Los Angeles, California, USA; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
Department of Pathology, School of Medicine, University of Southern California, Los Angeles, California, USA.
J Invest Dermatol. 2018 Sep;138(9):2041-2050. doi: 10.1016/j.jid.2018.02.043. Epub 2018 Mar 23.
Cutaneous wounds in adult mammals typically heal by scarring. However, large full-thickness wounds undergo wound-induced hair follicle neogenesis (WIHN), a form of regeneration. Here, we show that WIHN requires transient expression of epidermal Msx2 in two phases: the wound margin early and the wound center late. Msx2 expression is present in the migrating epithelium during early wound healing and then presents in the epithelium and mesenchyme later in the wound center. WIHN is abrogated in germline and epithelial-specific Msx2 mutant mice. Unlike the full-length Msx2 promoter, a minimal Msx2 promoter fails activation in the wound center, suggesting complex regulation of Msx2 expression. The Msx2 promoter binding sites include Tcf/Lef, Jun/Creb, Pax3, and three SMAD sites. However, basal epithelial-induced BMP suppression by noggin overexpression did not affect WIHN. We propose that Msx2 signaling is required for the epidermis to acquire spatiotemporal competence during WIHN. Topologically, hair regeneration dominates in the wound center, coinciding with late Msx2 expression. Together, these results suggest that intrinsic Msx2 expression supports epithelial competency during hair follicle neogenesis. This work provides insight into endogenous mechanisms modulating competency of adult epidermal progenitors for mammalian ectodermal appendage neogenesis, and offers the target Msx2 for future regeneration-promoting therapies.
成年哺乳动物的皮肤创伤通常会通过瘢痕愈合。然而，大面积全层创伤会经历创伤诱导的毛囊新生（WIHN），这是一种再生形式。在这里，我们表明 WIHN 需要表皮 Msx2 的瞬时表达，分为两个阶段：创伤边缘早期和创伤中心晚期。Msx2 表达存在于早期创伤愈合过程中的迁移上皮中，然后存在于创伤中心后期的上皮和间充质中。WIHN 在种系和上皮特异性 Msx2 突变小鼠中被废除。与全长 Msx2 启动子不同，最小的 Msx2 启动子在创伤中心无法激活，表明 Msx2 表达受到复杂的调控。Msx2 启动子结合位点包括 Tcf/Lef、Jun/Creb、Pax3 和三个 SMAD 位点。然而，通过 noggin 过表达抑制基础上皮诱导的 BMP 并不能影响 WIHN。我们提出，Msx2 信号对于表皮在 WIHN 期间获得时空能力是必需的。从拓扑学上讲，毛发再生在创伤中心占主导地位，与晚期 Msx2 表达一致。综上所述，这些结果表明内在的 Msx2 表达支持毛囊新生过程中表皮祖细胞的上皮能力。这项工作为调节哺乳动物外胚层附属物新生的成年表皮祖细胞能力的内源性机制提供了深入的了解，并为未来的再生促进治疗提供了目标 Msx2。
