Satoh Akira, Kashimoto Rena, Ohashi Ayaka, Furukawa Saya, Yamamoto Sakiya, Inoue Takeshi, Hayashi Toshinori, Agata Kiyokazu
Research Core for Interdisciplinary Sciences (RCIS), Okayama University, 3-1-1, Tsushima-naka, Kitaku, Okayama, 700-8530, Japan.
Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.
Zoological Lett. 2022 Apr 28;8(1):6. doi: 10.1186/s40851-022-00190-6.
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.
有尾两栖动物，如疣螈和墨西哥钝口螈，具有器官水平的再生能力，比如肢体再生。在两栖动物肢体再生过程中，多能细胞是由一种内源性机制诱导产生的。众所周知，真皮成纤维细胞接收再生信号并转变为多能细胞，即芽基细胞。然而，成熟真皮细胞向芽基细胞的诱导机制尚不清楚。我们之前发现，骨形态发生蛋白2（BMP2）、成纤维细胞生长因子2（FGF2）和成纤维细胞生长因子8（FGF8）（B2FF）在有尾两栖动物的芽基诱导中可发挥充分作用。在此，我们表明B2FF处理可诱导真皮来源的细胞参与肢体再生中的多种细胞谱系。我们首先建立了一种蝾螈真皮来源的细胞系，并证实对蝾螈细胞进行B2FF处理可使肢体再生中的细胞分化具有可塑性。为了阐明能够提供分化可塑性的因素，我们对蝾螈细胞和小鼠细胞进行了种间比较分析，发现仅在蝾螈细胞中，B2FF处理会上调磷酸二酯酶4B（Pde4b）基因。用化学磷酸二酯酶抑制剂阻断PDE4B信号可抑制真皮向软骨的转化，并且镶嵌基因敲除动物显示出一致的结果。我们的研究结果对于深入了解在两栖动物肢体再生早期阶段真皮成纤维细胞如何通过内源性程序获得多能性具有重要意义。
