STAT3 Controls the Long-Term Survival and Phenotype of Repair Schwann Cells during Nerve Regeneration.
STAT3 Controls the Long-Term Survival and Phenotype of Repair Schwann Cells during Nerve Regeneration.
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DOI：
10.1523/jneurosci.3481-16.2017
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发表时间：
2017-04-19
期刊：
影响因子：
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通讯作者：
Jessen KR
中科院分区：
文献类型：
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作者：
Benito C;Davis CM;Gomez-Sanchez JA;Turmaine M;Meijer D;Poli V;Mirsky R;Jessen KR
神经损伤后，雪旺细胞转化为专门促进修复的表型。但在轴突再生的缓慢过程中，这些修复的雪旺细胞逐渐失去支持再生的功能，最终死亡。虽然这是人类频繁再生失败的一个关键原因，但控制修复细胞长期存活和表型的转录机制尚未被研究，其衰退背后的分子信号也尚不清楚。我们发现，在小鼠身上，雪旺细胞STAT3具有双重作用。它支持修复雪旺细胞的长期存活，是维持修复雪旺细胞特性所必需的。相反，STAT3对损伤后修复雪旺细胞的初始生成不那么重要。在修复雪旺细胞中，我们发现在长期失神经过程中，由Tyr705磷酸化激活的雪旺细胞STAT3是持续的。STAT3是维持自分泌雪旺细胞生存信号所必需的，而雪旺细胞STAT3的失活会导致慢性失神经远端残端的修复细胞显著丧失。STAT3失活还会导致修复细胞和再生轨迹的形态异常，以及修复细胞标志物Shh、GDNF和BDNF的表达失败。由于雪旺细胞的发育在没有STAT3的情况下正常进行，因此该因子的功能似乎仅限于损伤后的雪旺细胞。这种支持修复细胞长期存活和分化的转录机制的识别将有助于识别并最终纠正导致这一重要细胞群退化的失败。意义声明虽然受损的周围神经含有修复雪旺细胞，为促进再生提供信号和空间线索，但神经损伤后的临床结果往往很差。一个关键原因是，在轴突通过受损神经修复的近端缓慢生长期间，雪旺细胞逐渐失去支持再生的功能，最终死亡。因此，识别维持修复细胞的信号是一个重要的目标。我们发现，在小鼠中，转录因子STAT3保护这些细胞免于死亡，并有助于维持促进轴突再生的分子和形态修复表型。确定维持雪旺细胞修复的分子机制是开发改善神经再生和功能恢复的治疗策略的关键一步。
After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population. SIGNIFICANCE STATEMENT Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal parts of injured nerves repair, Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step toward developing therapeutic strategies that improve nerve regeneration and functional recovery.