Nerves and Proliferation of Progenitor Cells in Limb Regeneration

Abstract

Nerves, in conjunction with the apical epidermal cap (AEC), play an important role in the proliferation of the mesenchymal progenitor cells comprising the blastema of regenerating urodele amphibian limbs. Reinnervation after amputation requires factors supplied by the forming blastema, and neurotrophic factors must be present at or above a quantitative threshold for mitosis of the blastema cells. The AEC forms independently of nerves, but requires nerves to be maintained. Urodele limb buds are independent of nerves for regeneration, but innervation imposes a regenerative requirement for nerve factors on their cells as they differentiate. There are three main ideas on the functional relationship between nerves, AEC, and blastema cells: (1) nerves and AEC produce factors with different roles in maintaining progenitor status and mitosis; (2) the AEC produces the factors that promote blastema cell mitosis, but requires nerves to express them; (3) blastema cells, nerves, and AEC all produce the same factor(s) that additively attain the required threshold for mitosis.

Evolution of epimorphosis in mammals

“…Both salamander limb regeneration and mouse digit tip regeneration are nerve‐dependent; denervation before amputation inhibits the regeneration response (Johnston et al, 2016; Satoh et al, 2015; Takeo et al, 2013). In salamanders, peripheral nerves readily regenerate, the limb blastema is highly innervated and the neurotrophic influence on limb regeneration is mediated by factors produced by regenerating axons or induced in cells associated with regenerating axons (Stocum, 2019). The regenerating axons produce FGF2 and BMP2 (Satoh, Makanae, Nishimoto, & Mitogawa, 2016) and downstream factors include anterior gradient (AG) protein which is produced by Schwann cells and signals via the Prod1 receptor, a member of the three‐finger protein superfamily, that regulates proximal–distal patterning during limb regeneration (da Silva, Gates, & Brockes, 2002; Kumar, Godwin, Gates, Garza‐Garcia, & Brockes, 2007).…”

“…Wound closure in limb regeneration is rapid and the wound epithelium is transformed into a signaling center called the apical epithelial cap (AEC) by activities associated with regenerating nerves that can be replaced using a cocktail of growth factors including FGFs and BMPs (Satoh et al, 2015). AEC formation is innervation‐dependent and coordinates blastema cell recruitment as well as stimulating cell proliferation (Satoh, Mitogawa, & Makanae, 2018; Stocum, 2019). In mouse digit tip blastema formation, the wound epidermis does not form until after osteoclast‐mediated bone resorption and wound closure occur beneath the necrotic stump bone that is cast‐off (Fernando et al, 2011).…”

From Cell Death to Regeneration: Rebuilding After Injury

“…Although the specific roles of apoptosis in regeneration are still being explored, it is known that apoptosis can drive proliferation during regeneration in Hydra, planaria, Xenopus, and zebrafish. As proliferation is a critical aspect of regeneration (Gargioli and Slack, 2004;Jopling et al, 2010;Stocum, 2019), apoptosis is therefore an important regulator of regeneration.…”

Model systems for regeneration: the spiny mouse, Acomys cahirinus

“…The proximal semicircle of the punch wound has a plentiful supply of axons from the auricular nerve, but the axons in the distal semicircle of the wound are severed, making the distal part effectively denervated. The role of nerves in axolotl limb regeneration is well established (Stocum, 2019) and acts via the axonal and probably Schwann cell-based synthesis of the growth factor Neuregulin 1, which is released into the blastemal milieu to stimulate blastemal cell proliferation (Farkas et al, 2016). It would be of great interest to determine whether Neuregulin 1 is present in the Acomys auricular nerve and whether its inhibition prevents ear hole regeneration.…”