Epidermal closure regulates histolysis during mammalian (Mus) digit regeneration

Abstract

Mammalian digit regeneration progresses through consistent stages: histolysis, inflammation, epidermal closure, blastema formation, and finally redifferentiation. What we do not yet know is how each stage can affect others. Questions of stage timing, tissue interactions, and microenvironmental states are becoming increasingly important as we look toward solutions for whole limb regeneration. This study focuses on the timing of epidermal closure which, in mammals, is delayed compared to more regenerative animals like the axolotl. We use a standard wound closure device, Dermabond (2‐octyl cyanoacrylate), to induce earlier epidermal closure, and we evaluate the effect of fast epidermal closure on histolysis, blastema formation, and redifferentiation. We find that fast epidermal closure is reliant upon a hypoxic microenvironment. Additionally, early epidermal closure eliminates the histolysis stage and results in a regenerate that more closely replicates the amputated structure. We show that tools like Dermabond and oxygen are able to independently influence the various stages of regeneration enabling us to uncouple histolysis, wound closure, and other regenerative events. With this study, we start to understand how each stage of mammalian digit regeneration is controlled.

Analogous cellular contribution and healing mechanisms following digit amputation and phalangeal fracture in mice

“…This suggests that the endochondral ossification response of the periosteum is triggered by an early bone degradation event and supports the general model that tissue histolysis is required for the release and/or activation of progenitor cells necessary for a regenerative response (Simkin et al. ).…”

Trends in tissue repair and regeneration

“…Ken Muneoka (Texas A&M University, USA) found that digit regeneration in mice, which is enhanced when the wound remains open, is preceded by histolysis and bone resorption in the stump. Bone resorption is a crucial initiator of the regenerative process: it regulates blastema size and thus the extent of regeneration (Simkin et al, 2015). His laboratory has also established a new experimental model in which a simple wound of the nail triggers bone resorption and a regenerative response.…”

The mammalian blastema: regeneration at our fingertips

“…These trabecular spaces are continuously remodeled with time. (A) is reprinted from Simkin et al () and (C) is reprinted from Fernando et al ().…”

“…One role that the wound epidermis plays in regulating the early events of blastema formation has been uncovered by experimentally altering the rate of wound closure (Simkin et al 2015). The use of cyanoacrylates as a wound dressing in mammals improves the wound healing response in part by increasing the rate of epidermal closure (Singer & Thode 2004;Nipshagen et al 2008;Singer et al 2008;Wachter et al 2010).…”