Nerve dependence in tissue, organ, and appendage regeneration

Abstract

Many regeneration contexts require the presence of regenerating nerves as a transient component of the progenitor cell niche. Here we review nerve involvement in regeneration of various structures in vertebrates and invertebrates. Nerves are also implicated as persistent determinants in the niche of certain stem cells in mammals, as well as in Drosophila. We consider our present understanding of the cellular and molecular mechanisms underlying nerve dependence, including evidence of critical interactions with glia and non-neural cell types. The example of the salamander aneurogenic limb illustrates that developmental interactions between the limb bud and its innervation can be determinative for adult regeneration. These phenomena provide a different perspective on nerve cells to that based on chemical and electrical excitability.

Getting nervous about regeneration

“…A FGF8-SHH circuit encoding positional information was identified in the regenerating salamander limb (13). The requirement of PNS innervation for regeneration competence of appendages has been well documented in fish and salamanders (1,9,(14)(15)(16)(17), while denervation experiments in a rodent model found that regeneration in the absence of nerves results in an abbreviated regenerate with abnormal patterning (1). Yet, as no evidence of a specific cellular and molecular contribution of the PNS to the mammalian regenerative process had previously been reported, the experiments performed by Johnston et al demonstrate the necessity of Schwann cells in multiple mammalian models of regeneration, including dermal wound healing and digit tip regeneration, and are thus of particular relevance to tissue engineering and regenerative medicine.…”

Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration

“…Urodeles regenerate entire limbs by proliferation of fate-restricted stem and progenitor cells and form a blastema, the collection of cells at the interface of stump and wound epidermis, in a process mediated by nerve-derived factors (6)(7)(8)(9)(10). In Urodeles, surgical denervation before amputation results in the inhibition of blastema formation, and ultimately results in regeneration failure.…”

Adenosine enhances progenitor cell recruitment and nerve growth via its A2B receptor during adult fin regeneration

“…Recent studies have shown that purinergic signalling is a key element in cell proliferation [32][33][34][35] and in nerve physiology [36][37][38]. Finally, ATP is an essential molecule in the communication between neuron and glia [39], an essential function in systems in which regeneration is nerve-dependent [40,14].…”

“…It is well known that innervation plays a crucial role in blastema formation and growth [12,13] (for review, see [48,1,14]). As adenosine is a key regulator of neuron physiology [49,50], we analysed the impact of apoptosis inhibition and adenosine treatment on sensory neuron regrowth after amputation (Fig.…”

“…The missing structure will be replaced through blastema growth differentiation and morphogenesis. In regenerative models, the replacement of damaged organs or appendices requires the coordination of three modules: an early module that corresponds to the early injury response [7]; a second module that is interlocked with the first module and one that still needs to be clarified but includes apoptosis and reactive oxygen species (ROS) signalling [8][9][10][11] and is nerve-dependant [12][13][14]; and the last module, which corresponds to blastema growth and developmental programmes to be activated again to drive the differentiation and morphogenesis of a correct structure [1,15]. Crucial questions that remain unanswered include how amputation drives the dedifferentiation of cells into a progenitor state and the nature of the signalling system that induces their recruitment and migration to form the blastema [16].…”