Fibroblast dedifferentiation as a determinant of successful regeneration.
Fibroblast dedifferentiation as a determinant of successful regeneration.
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DOI：
10.1016/j.devcel.2021.04.016
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发表时间：
2021-05-17
影响因子：
11.8
通讯作者：
Tanaka EM
中科院分区：
文献类型：
--
作者：
Lin TY;Gerber T;Taniguchi-Sugiura Y;Murawala P;Hermann S;Grosser L;Shibata E;Treutlein B;Tanaka EM
四肢再生，而观察终身在蝾螈，是有限的后变质非洲爪蟾蛙。这种丧失是由于系统性因素还是细胞内在的不能形成有能力的干细胞尚不清楚。在这里，我们使用遗传的命运映射，以建立结缔组织（CT）细胞形成后变质的青蛙芽基，在蝾螈的情况下。使用异时移植到肢芽和单细胞转录组学分析，我们表明，蝾螈CT细胞去分化和整合，形成谱系，包括软骨。相比之下，青蛙芽基CT细胞不完全重新表达肢芽祖程序，即使移植到肢芽。相应地，移植的细胞有助于软骨外CT，但不发育软骨。此外，使用单细胞RNA-seq分析，我们发现胚胎和成年青蛙软骨分化程序在分子上是不同的。这项工作将CT去分化的内在限制定义为成体再生的限制。成纤维细胞衍生的Prrx 1+细胞是青蛙肢体芽基的主要组成部分青蛙成纤维细胞由于内在的限制只经历部分去分化成人软骨形成是不同于胚胎程序Lin et al.系统地比较了蝾螈和非洲爪蛙对截肢的反应。与蝾螈不同，青蛙肢体成纤维细胞不能完全重新激活肢体再生所需的发育程序。这项工作将成纤维细胞的内在限制定义为成体再生的限制。
Limb regeneration, while observed lifelong in salamanders, is restricted in post-metamorphic Xenopus laevis frogs. Whether this loss is due to systemic factors or an intrinsic incapability of cells to form competent stem cells has been unclear. Here, we use genetic fate mapping to establish that connective tissue (CT) cells form the post-metamorphic frog blastema, as in the case of axolotls. Using heterochronic transplantation into the limb bud and single-cell transcriptomic profiling, we show that axolotl CT cells dedifferentiate and integrate to form lineages, including cartilage. In contrast, frog blastema CT cells do not fully re-express the limb bud progenitor program, even when transplanted into the limb bud. Correspondingly, transplanted cells contribute to extraskeletal CT, but not to the developing cartilage. Furthermore, using single-cell RNA-seq analysis we find that embryonic and adult frog cartilage differentiation programs are molecularly distinct. This work defines intrinsic restrictions in CT dedifferentiation as a limitation in adult regeneration. Fibroblast-derived Prrx1+ cells are the main constituent of a frog limb blastema Frog fibroblasts only undergo partial dedifferentiation due to intrinsic limitations Adult chondrogenesis is distinct from the embryonic program Lin et al. systematically compared the response to limb amputation in axolotls and African clawed frogs. Unlike in axolotls, frog limb fibroblasts are incapable of fully re-activating developmental programs required for complete limb regeneration. This work defines intrinsic restrictions in fibroblasts as a limitation to adult regeneration.