Deconstructing reprogramming competence: role of reactive gliosis and proliferation in glia-to-neuron conversion

解构重编程能力：反应性神经胶质增生和增殖在神经胶质细胞向神经元转化中的作用

• 批准号: 530079744
• 负责人: Professor Dr. Benedikt Berninger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530079744?language=en
• 关键词: Deconstructing; reprogramming; competence; role; reactive

Lineage reprogramming of cell identity is an emerging concept for the remodelling and restoration of organs with limited regenerative capacity. In the context of neurological disease, this concept opens the possibility of regenerating neurons from other brain-resident cell types such as glial cells for the repair of diseased brain circuits. Over the past years, we and others have shown that various types of glial cells can be converted into induced neurons (iNs) in vitro and in vivo by forced expression of neurogenic transcription factors. In a recent collaboration between the French and German partners, we succeeded in showing that iNs induced from reactive glia during early stages of the disease can reduce seizure activity in a mouse model of Mesial Temporal Lobe Epilepsy (MTLE). While this opens exciting possibilities, a key question is whether the competence of glial cells to undergo reprogramming into iNs is restricted to reactive glia during early epileptogenesis or can still be induced during the chronic phase when the disease is firmly established. In fact, what confers reprogramming competence to reactive glial cells and whether reprogramming competence can be boosted in glia which has become refractory to neuronal conversion is currently unknown. To address these important questions, in FateXchange, we will therefore tackle the following complementary aims: i) Aim 1: Determine the impact of the transcriptional and chromatin landscapes of reactive glial cell types on reprogramming competence during hippocampal epileptogenesis; ii) Aim 2: Promote reprogramming competence of glia during chronic MTLE. Thus, FateXchange may yield innovative strategies of remodelling brain circuits during chronic disease stages, thereby addressing challenges currently impeding translation of lineage reprogramming to clinical demands.

细胞身份的谱系重编程是一个新兴的概念，用于重塑和恢复再生能力有限的器官。在神经系统疾病的背景下，这一概念开辟了从其他脑驻留细胞类型（如神经胶质细胞）再生神经元的可能性，以修复患病的脑回路。在过去的几年里，我们和其他人已经表明，各种类型的神经胶质细胞可以转化为诱导神经元（iNs）在体外和体内通过强制表达的神经源性转录因子。在法国和德国合作伙伴最近的一次合作中，我们成功地表明，在疾病的早期阶段，反应性胶质细胞诱导的iNs可以减少内侧颞叶癫痫（MTLE）小鼠模型的癫痫发作活动。虽然这开启了令人兴奋的可能性，但一个关键问题是神经胶质细胞进行重编程为iN的能力是否仅限于早期癫痫发生期间的反应性神经胶质细胞，或者当疾病牢固建立时，仍然可以在慢性期诱导。事实上，是什么赋予反应性神经胶质细胞重编程能力，以及重编程能力是否可以在神经胶质细胞中增强，这已经成为难治性神经元转换目前是未知的。为了解决这些重要问题，在FateXchange中，我们将解决以下互补目标：i）目标1：确定海马癫痫发生期间反应性胶质细胞类型的转录和染色质景观对重编程能力的影响; ii）目标2：促进慢性MTLE期间胶质细胞的重编程能力。因此，FateXchange可能会产生在慢性疾病阶段重塑脑回路的创新策略，从而解决目前阻碍谱系重编程转化为临床需求的挑战。