Epimorphic regeneration of the mouse digit tip is finite

Connor P Dolan,Tae-Jung Yang,Dana Gaddy,Regina Brunauer,Joshua Gregory,Osama Qureshi,Larry J Suva,Lindsay A Dawson,Benjamin Daniel,Ling Yu,Felisha Imholt,Macie Mayes,Hannah Koester,Katherine Zimmel,Mingquan Yan,Kayla Ritchie,Ken Muneoka,Alyssa Falck

doi:10.1186/s13287-022-02741-2

Abstract

BackgroundStructural regeneration of amputated appendages by blastema-mediated, epimorphic regeneration is a process whose mechanisms are beginning to be employed for inducing regeneration. While epimorphic regeneration is classically studied in non-amniote vertebrates such as salamanders, mammals also possess a limited ability for epimorphic regeneration, best exemplified by the regeneration of the distal mouse digit tip. A fundamental, but still unresolved question is whether epimorphic regeneration and blastema formation is exhaustible, similar to the finite limits of stem-cell mediated tissue regeneration.MethodsIn this study, distal mouse digits were amputated, allowed to regenerate and then repeatedly amputated. To quantify the extent and patterning of the regenerated digit, the digit bone as the most prominent regenerating element in the mouse digit was followed by in vivo µCT.ResultsAnalyses revealed that digit regeneration is indeed progressively attenuated, beginning after the second regeneration cycle, but that the pattern is faithfully restored until the end of the fourth regeneration cycle. Surprisingly, when unamputated digits in the vicinity of repeatedly amputated digits were themselves amputated, these new amputations also exhibited a similarly attenuated regeneration response, suggesting a systemic component to the amputation injury response.ConclusionsIn sum, these data suggest that epimorphic regeneration in mammals is finite and due to the exhaustion of the proliferation and differentiation capacity of the blastema cell source.

Highlights

Structural regeneration of amputated appendages by blastema-mediated, epimorphic regeneration is a process whose mechanisms are beginning to be employed for inducing regeneration
The results indicate that repeated amputations exhaust the local cell source to produce a functional blastema, and induce systemic changes that are unfavorable for the epimorphic regeneration of previously uninjured tissues
Mouse digit tip regeneration is exhaustible To determine the extent to which mouse digits can continually regenerate after repeated amputations, the distal digit tips of the 2nd and 4th hindlimb digits were amputated on each hindlimb (n = 40 digits/10 mice)

Summary

Introduction

Structural regeneration of amputated appendages by blastema-mediated, epimorphic regeneration is a process whose mechanisms are beginning to be employed for inducing regeneration. While epimorphic regenera‐ tion is classically studied in non-amniote vertebrates such as salamanders, mammals possess a limited ability for epimorphic regeneration, best exemplified by the regeneration of the distal mouse digit tip. A fundamental, but still unresolved question is whether epimorphic regeneration and blastema formation is exhaustible, similar to the finite limits of stem-cell mediated tissue regeneration. In contrast to stem-cell mediated reparative tissue regeneration, epimorphic regeneration is a structural regeneration mode that enables vertebrates to regrow all tissues of an amputated structure in a patterned fashion by de novo morphogenesis. Epimorphic regeneration is mediated by a blastema that forms by either dedifferentiation or recruitment of tissue-resident stem cells, or a combination of both, as appears to be the case in the mammalian digit tip [9,10,11]. It is impossible to generalize about the limitations of epimorphic regeneration

Methods

Results

Conclusion