Maan Zeshaan N, Rinkevich Yuval, Barrera Janos, Chen Kellen, Henn Dominic, Foster Deshka, Bonham Clark Andrew, Padmanabhan Jagannath, Sivaraj Dharshan, Duscher Dominik, Hu Michael, Yan Kelley, Januszyk Michael, Longaker Michael T, Weissman Irving L, Gurtner Geoffrey C
Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
J Clin Med. 2021 Sep 20;10(18):4261. doi: 10.3390/jcm10184261.
Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans.
手部损伤常导致严重的功能障碍，且很少能完全恢复。例如，蝾螈和火蜥蜴等动物受伤肢体能够自发再生，人类指尖远端截肢后也有过此类再生的报道，但这种再生在哺乳动物中较为罕见，且人们对此尚未完全了解。在此，我们通过切除小鼠指尖来研究指尖再生，切除部位要么在远端以启动再生，要么在近端以引发纤维化。通过无偏倚微阵列分析，我们发现指尖再生与毛囊分化、Wnt和音猬因子（SHH）信号通路显著相关。病毒过表达和基因敲除实验表明了这些信号通路在再生过程中的功能重要性。利用转基因报告小鼠，我们证明，虽然经典Wnt信号和HH信号都局限于表皮组织，但下游的刺猬信号（通过Gli）发生在间充质组织中。这些发现揭示了在指再生过程中，由经典刺猬信号调控的表皮/间充质相互作用机制。对这些信号通路的进一步研究可能会改善人类手部损伤后的治疗效果。
