Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Next Generation Sequencing Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Int J Mol Sci. 2024 Nov 19;25(22):12440. doi: 10.3390/ijms252212440.
Stroke is one of the leading causes of chronic disability in humans. It has been proposed that the endogenous neural stem/progenitor cells generate new neurons in the damaged area. Still, the contribution of these cells is negligible because a low number of newborn mature neurons are formed. conventional knock-out mice, -CreERT2 mice, and -overexpressing (-OE) mice were specifically chosen for their unique genetic characteristics, which were crucial for the experiments. Permanent and transient middle cerebral artery occlusion was used to induce stroke in the mice. Immunostainings for doublecortin and GFP/BrdU/NeuN were performed to study neurogenesis and fate mapping. The rotarod test was performed to assess motor deficits. Here, we show that stroke-induced neurogenesis is dramatically increased with the additional expression of two copies of the nuclear receptor-coding gene (, also known as ), which has been shown to be a master regulator of subventricular zone (SVZ) neural stem cells (NSCs). We show that expression is upregulated after stroke, and stroke-induced neurogenesis is blocked when is inactivated. overexpression in NSCs leads to massive induction of neurogenesis via stroke. More newborn mature neurons are formed in -overexpressing mice, leading to improved coordination and motor function recovery. Most importantly, we also demonstrate that this process is sustained in aged mice, where stroke-induced neurogenesis is nearly undetectable in wild-type animals. This study provides the first stem cell-specific genetic evidence that endogenous NSCs can be exploited by manipulating their master regulator, , and thus suggests a novel therapeutic strategy for neuronal repair.
中风是导致人类慢性残疾的主要原因之一。据推测，内源性神经干细胞/祖细胞会在受损区域产生新的神经元。然而，这些细胞的贡献微不足道，因为只有极少数的新生成熟神经元形成。本研究选择了传统的基因敲除（KO）小鼠、-CreERT2 小鼠和过表达（OE）小鼠，它们具有独特的遗传特征，对实验至关重要。永久性和短暂性大脑中动脉闭塞被用于诱导小鼠中风。利用双重皮质酮和 GFP/BrdU/NeuN 免疫染色来研究神经发生和命运图谱。通过转棒试验来评估运动缺陷。本研究表明，额外表达两个核受体编码基因（也称为）可显著增加中风诱导的神经发生，该基因已被证明是侧脑室下区（SVZ）神经干细胞（NSC）的主要调节因子。研究表明，中风后 表达上调，当 失活时，中风诱导的神经发生被阻断。NSC 中的 过表达可通过中风导致大量的神经发生。在 -OE 小鼠中形成了更多的新生成熟神经元，导致协调和运动功能恢复得到改善。最重要的是，我们还证明了这个过程在老年小鼠中是持续的，在野生型动物中，中风诱导的神经发生几乎检测不到。本研究提供了第一个干细胞特异性的遗传证据，表明内源性 NSCs 可以通过操纵其主调控因子 来利用，从而为神经元修复提供了一种新的治疗策略。
