The Wound Microenvironment Reprograms Schwann Cells to Invasive Mesenchymal-like Cells to Drive Peripheral Nerve Regeneration.
The Wound Microenvironment Reprograms Schwann Cells to Invasive Mesenchymal-like Cells to Drive Peripheral Nerve Regeneration.
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DOI：
10.1016/j.neuron.2017.09.008
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发表时间：
2017-09-27
期刊：
影响因子：
16.2
通讯作者：
Parrinello S
中科院分区：
文献类型：
--
作者：
Clements MP;Byrne E;Camarillo Guerrero LF;Cattin AL;Zakka L;Ashraf A;Burden JJ;Khadayate S;Lloyd AC;Marguerat S;Parrinello S
雪旺细胞从髓鞘细胞到祖细胞样细胞的脱分化是周围神经损伤后显著再生能力的基础。然而，分化和去分化状态在体内的分子特性一直是难以捉摸的。在这里，我们描述了从完整神经和从伤口和远端切断神经区域急性纯化的雪旺细胞。我们的分析揭示了去分化反应的新方面，包括间充质性状的获得和Myc模块。此外，伤口和远端去分化的雪旺细胞构成不同的群体，伤口细胞在局部tgf - β信号诱导下表现出增强的间质特性。TGFβ通过n -钙粘蛋白促进Eph信号的侵袭和串串，驱动雪旺细胞在伤口上的集体迁移。一致地，雪旺细胞中的Tgfbr2缺失导致定向错误和延迟的神经再生。因此，伤口微环境是雪旺细胞身份的关键决定因素，它通过整合多种协同信号促进神经修复。创伤雪旺细胞具有独特的去分化程序tgf - β信号转导将创伤雪旺细胞重编程为侵袭性间质样细胞tgf - β与Eph信号交叉，驱动雪旺细胞集体迁移。雪旺细胞中tgf - β信号转导的缺失延迟了神经再生Clements等人表明，神经损伤诱导的雪旺细胞去分化程序是由伤口微环境通过tgf - β调节的。TGFβ通过将雪旺细胞重编程为侵袭性间充质样细胞，并与Eph信号串扰以驱动集体迁移，从而促进再生。
Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals. Wound Schwann cells have a distinct dedifferentiation program TGFβ signaling reprograms wound Schwann cells to invasive mesenchymal-like cells TGFβ crosstalks with Eph signaling to drive collective Schwann cell migration Loss of TGFβ signaling in Schwann cells delays nerve regeneration Clements et al. show that the nerve-injury-induced Schwann cell dedifferentiation program is modulated by the wound microenvironment through TGFβ. TGFβ promotes regeneration by reprogramming Schwann cells to invasive, mesenchymal-like cells and crosstalking with Eph signaling to drive collective migration.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
20.3
作者：
Levéen, P;Larsson, J;Karlsson, S
通讯作者：
Karlsson, S
影响因子：
--
作者：
Mcdonald, David;Cheng, Chu;Zochodne, Douglas
通讯作者：
Zochodne, Douglas
影响因子：
5.3
作者：
D'Antonio, Maurizio;Droggiti, Anna;Jessen, Kristjan R.
通讯作者：
Jessen, Kristjan R.
影响因子：
16.2
作者：
Napoli, Ilaria;Noon, Luke A.;Lloyd, Alison C.
通讯作者：
Lloyd, Alison C.