start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=1 article-no= start-page=6 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220428 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=An approach for elucidating dermal fibroblast dedifferentiation in amphibian limb regeneration en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=SatohAkira en-aut-sei=Satoh en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KashimotoRena en-aut-sei=Kashimoto en-aut-mei=Rena kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiAyaka en-aut-sei=Ohashi en-aut-mei=Ayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FurukawaSaya en-aut-sei=Furukawa en-aut-mei=Saya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamamotoSakiya en-aut-sei=Yamamoto en-aut-mei=Sakiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=InoueTakeshi en-aut-sei=Inoue en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HayashiToshinori en-aut-sei=Hayashi en-aut-mei=Toshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AgataKiyokazu en-aut-sei=Agata en-aut-mei=Kiyokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Research Core for Interdisciplinary Sciences (RCIS), Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Envi�ronmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Envi�ronmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=Faculty of Science, Department of Biological Sciences, Okayama University kn-affil= affil-num=5 en-affil=Faculty of Science, Department of Biological Sciences, Okayama University kn-affil= affil-num=6 en-affil=Division of Adaptation Physiology, Faculty of Medicine, Tottori University kn-affil= affil-num=7 en-affil=Amphibian Research Center, Hiroshima University kn-affil= affil-num=8 en-affil=Laboratory of Regeneration Biology, National Institute for Basic Biology kn-affil= en-keyword=Pde4b kn-keyword=Pde4b en-keyword=Limb regeneration kn-keyword=Limb regeneration en-keyword=Pleurodels waltl kn-keyword=Pleurodels waltl en-keyword=Ambystoma mexicanum kn-keyword=Ambystoma mexicanum en-keyword=Dedifferentiation kn-keyword=Dedifferentiation en-keyword=Reprogramming kn-keyword=Reprogramming END