Fluctuation of cellular differentiation in limb regeneration is regulated by Pde4b in urodele amphibians

Urodele amphibians, Pleurodeles waltl and Ambystoma mexicanum, have
organ-level regeneration capability, such as limb regeneration.
Multipotent cells are induced by an endogenous mechanism in amphibian limb
regeneration. It is well known that dermal fibroblasts receive
regenerative signals and turn into multipotent cells, called blastema
cells. However, the induction mechanism of the blastema cells from matured
dermal cells was unknown. We previously found that BMP2, FGF2, and FGF8
(B2FF) could play sufficient roles in blastema induction in urodele
amphibians. Here, we show that B2FF treatment can induce dermis-derived
cells that can participate in multiple cell lineage in limb regeneration.
We first established a newt dermis-derived cell line and confirmed that
B2FF treatment on the newt cells provided plasticity in cellular
differentiation in limb regeneration. To clarify the factors that can
provide the plasticity in differentiation, we performed the interspecies
comparative analysis between newt cells and mouse cells and found the
Pde4b gene was upregulated by B2FF treatment only in the newt cells.
Blocking PDE4B signaling by a chemical PDE4 inhibitor suppressed
dermis-to-cartilage transformation and the mosaic knockout animals showed
consistent results. Our results are a valuable insight into how dermal
fibroblasts acquire multipotency during the early phase of limb
regeneration via an endogenous program in amphibian limb regeneration.