Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs.
Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs.
复制标题
分泌抑制剂驱动爪蟾肢体再生能力的丧失。
DOI：
10.1242/dev.199158
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发表时间：
2021-06-01
期刊：
影响因子：
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通讯作者：
Simons BD
中科院分区：
文献类型：
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作者：
Aztekin C;Hiscock TW;Gurdon J;Jullien J;Marioni J;Simons BD
在高等脊椎动物中，缺乏专门的伤口表皮被假设为阻碍肢体再生。然而，阻止其在再生能力差的动物中形成的因素知之甚少。为了表征非洲爪蟾蝌蚪中专门伤口表皮形成的内源性分子和细胞调节剂，以及发育过程中再生能力的丧失，我们使用了单细胞转录组学和离体再生肢体培养。转录组学分析表明，专门的伤口表皮不是一种新的细胞状态，而是四肢发育的基础上的顶端-外胚层-嵴（AER）程序的重新部署。分泌的抑制因子的富集，包括Noggin，一种在发育中的软骨/骨祖细胞中表达的形态原，被鉴定为再生能力差的蝌蚪中AER细胞形成的关键抑制剂。这些因子可以被Fgf 10所覆盖，Fgf 10在Noggin的上游起作用并阻断软骨形成。这些结果表明，操纵细胞外环境和/或软骨形成可能提供一种策略，以恢复再生潜力的高等脊椎动物。总结：与软骨形成进展相关的分泌抑制剂抑制AER细胞形成并限制肢体再生潜力。
Absence of a specialized wound epidermis is hypothesized to block limb regeneration in higher vertebrates. However, the factors preventing its formation in regeneration-incompetent animals are poorly understood. To characterize the endogenous molecular and cellular regulators of specialized wound epidermis formation in Xenopus laevis tadpoles, and the loss of their regeneration competency during development, we used single-cell transcriptomics and ex vivo regenerating limb cultures. Transcriptomic analysis revealed that the specialized wound epidermis is not a novel cell state, but a re-deployment of the apical-ectodermal-ridge (AER) programme underlying limb development. Enrichment of secreted inhibitory factors, including Noggin, a morphogen expressed in developing cartilage/bone progenitor cells, are identified as key inhibitors of AER cell formation in regeneration-incompetent tadpoles. These factors can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. These results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates. Summary: Secreted inhibitors associated with chondrogenic progression inhibit AER cell formation and restrict limb regeneration potential.