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

细胞特性的谱系重新编程是对再生能力有限的器官进行重塑和修复的一个新兴概念。在神经系统疾病的背景下，这一概念开启了从其他脑驻留细胞类型再生神经元的可能性，例如神经胶质细胞，用于修复患病的大脑回路。在过去的几年里，我们和其他人已经证明，在体外和体内，通过强制表达神经源性转录因子，各种类型的胶质细胞都可以转化为诱导神经元(INS)。在法国和德国合作伙伴最近的一项合作中，我们成功地表明，在疾病的早期阶段，由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。虽然这带来了令人兴奋的可能性，但一个关键的问题是，神经胶质细胞重新编程为INS的能力是仅限于癫痫发生早期的反应性胶质细胞，还是仍然可以在疾病确立的慢性期诱导。事实上，目前还不清楚是什么赋予了反应性神经胶质细胞重编程能力，以及是否可以提高神经胶质细胞的重编程能力，因为胶质细胞对神经元转换已经变得难以实现。为了解决这些重要的问题，因此，在FateXchange中，我们将解决以下补充目标：i)目标1：确定反应性胶质细胞类型的转录和染色质景观在海马癫痫发生过程中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可能会产生在慢性病阶段重塑大脑回路的创新策略，从而解决目前阻碍谱系重新编程转换为临床需求的挑战。

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.