Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip

Abstract

Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.

Getting nervous about regeneration

“…Adam Johnston and colleagues at the University of Toronto have recently shed light on this process by defining the requirement for neural crestderived Schwann cells and demonstrating that their secreted cytokines can largely rescue regeneration in the absence of intact innervation (2). Here we review their specific results and discuss the broader implications for multi-tissue regeneration.…”

A brief history of the study of nerve dependent regeneration

“…11 In contrast, a 2016 study by Johnston et al indicated that Schwann cells dedifferentiate after amputation and secrete essential paracrine factors, including oncostatin M and PDGF-AA, that act to stimulate mesenchymal cell proliferation. 12 Study of the nerve dependency of ear hole-punch regeneration also remains in its early stages. Denervation leads to tissue regression and necrosis in mouse strains which are capable of healing ear wounds.…”

Spotlight on the Schwann cells during the regeneration

“…Moreover, this process is dependent on the innervations. In a more recent study by Johnston et al, it has been shown that the re-growth of an amputated mouse distal digit tip is dependent on the presence of Schwann cells that produce special molecules boosting regeneration and improving morphogenesis (11). Authors performed series of elegant experiments to demonstrate that upon injury, Schwann cells detach from the terminal axons in the affected site, dedifferentiate, undergo multiple cell divisions and secrete factors that attract mesenchymal cells thus supporting the blastema formation A similar logic has been previously described for regenerating salamander limb: Schwann cells from the transected nerve secrete nAG ligand that stimulates blastemal formation through binding to PROD in other cells of the limb (12).…”