Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.

中文翻译：

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室管膜细胞谱系重编程作为脑积水的潜在治疗干预措施。


脑积水是一种常见的神经系统疾病，其特征是脑脊液在脑室中过度积聚。脑积水的主要治疗主要涉及神经外科脑脊液分流，其发病率和失败率都很高，凸显了发现新治疗方法的必要性。尽管脑积水的病理生理学是高度多因素的，但脑室管膜细胞功能受损在脑积水中起着重要作用。在这里，我们表明 GemC1 和 McIdas 是多纤毛室管膜细胞命运决定的关键调节因子，诱导细胞对室管膜的直接重编程。我们的研究表明，GemC1 和 McIdas 的异位表达对皮质星形胶质细胞进行重编程，并将小鼠胚胎干细胞编程为室管膜。McIdas 足以在重编程的星形胶质细胞中建立功能活性。此外，我们表明 McIdas 的表达在两种不同的出生后脑积水小鼠模型中促进室管膜细胞再生：颅内出血和脑积水的遗传形式，并改善神经源性生态位的细胞结构。我们的研究提供了在模拟脑积水的动物模型中恢复室管膜的证据，可用于未来的治疗干预。