Epidermal-Derived Hedgehog Signaling Drives Mesenchymal Proliferation during Digit Tip Regeneration.

Dharshan Sivaraj,Irving L. Weissman,Janos Barrera,Michael T. Longaker,Kelley Yan,Deshka Foster,Zeshaan N. Maan,Kellen Chen,Dominic Henn,Geoffrey C. Gurtner,Jagannath Padmanabhan,Michael Hu,Yuval Rinkevich,Dominik Duscher,Michael Januszyk,Clark Andrew Bonham

doi:10.3390/jcm10184261

Abstract

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.

Highlights

The human hand is a powerful tool for interaction with the environment
This included a number of Krtap genes, which encode Keratin associated proteins associated with physiologic re-epithelialization and hair follicle development, as well as Wnt and HH signaling [23,24,25]
Two weeks following the amputation, we identified extensive clonal proliferation of HH-responsive mesenchymal cells within the regenerating digit tip (Figure 7B,C), suggesting that tissue-resident progenitor cells proliferate polyclonally in response to canonical hedgehog signaling during digit tip regeneration

Summary

Introduction

The human hand is a powerful tool for interaction with the environment. Amputation injuries affecting the hand and upper extremity can lead to severe functional impairment and affect almost every aspect of a person’s life. Even with expert surgical intervention and rigorous occupational therapy, it has proven challenging to fully restore pre-injury hand function due to the minimal regenerative capacity of the various tissue types that constitute the hand [1,2]. The fibrotic “patch” repair process restores the barrier between the body and the external environment but is largely devoid of native tissue properties. In a part of the body reliant on harmonious anatomic interplay, this leads to unsatisfactory functional outcomes [1,4,6]

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Discussion

Conclusion