Inhibiting fibroblast aggregation in skin wounds unlocks developmental pathway to regeneration

Abstract

Salamanders are capable of full-thickness skin regeneration where removal of epidermis, dermis and hypodermis results in scar-free repair. What remains unclear is whether regeneration of these tissues recapitulates the cellular events of skin development or occurs through a process unique to regenerative healing. Unfortunately, information on the post-embryonic development of salamander skin is severely lacking, having focused on compartments or cell types, but never on the skin as a complete organ. By examining coordinated development of the epidermis and dermis in axolotls we establish six distinct stages of skin development (I-VI): I-V for normally paedomorphic adults and a sixth stage following metamorphosis. Raising animals either in isolation (zero density pressure) or in groups (density pressure) we find that skin development progresses as a function of animal size and that density directly effects developmental rate. Using keratins, p63, and proliferative markers, we show that although the epidermis lacks visible stratification at early stages of skin development, when the dermis transforms into the stratum spongiosum and stratum compactum keratinocytes differentiate into at least three distinct phenotypes that reveal a cryptic stratification program uncoupled from metamorphosis. Lastly, comparing skin regeneration to skin development, we find that dermal regeneration occurs through a unique process, relying heavily on remodeling of the wound extracellular matrix, rather than proceeding through direct development of a dermal lamella produced by the epidermis. By preventing fibroblast influx into the wound bed using beryllium nitrate, we show that in the absence of fibroblast generated ECM production skin regeneration occurs through an alternate route that recapitulates development.

Integrin-driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

“…While regeneration shares mechanisms with embryonic development, the molecules involved are often different and spinal cord repair does not closely recapitulate development (Harty et al, 2003; Nacu and Tanaka, 2011; Seifert et al, 2019). A recent profiling study of peripheral nerve regeneration has found only minor correlation between the changes after peripheral axotomy and embryonic development (Renthal et al, 2020).…”

“…The issue of whether integrin-kindlin-driven regeneration represents a return to an embryonic pattern of expression is of obvious interest. In general, repair does not accurately recapitulate development (Harty et al, 2003; Nacu and Tanaka, 2011; Seifert et al, 2019), although basic mechanisms of cell movement are shared. In a previous study, embryonic recapitulation was marginally significant in peripheral nerve regeneration (Renthal et al, 2020).…”