Song Yanna, Li Haoyang, Li Yuhan, Xu Huiming, Nazir Faisal Hayat, Jiang Wei, Zheng Lu, Tang Changyong
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No.119, South 4th Ring Road West, Fengtai District, Beijing 100070, China.
Stem Cell Reports. 2025 Jan 14;20(1):102383. doi: 10.1016/j.stemcr.2024.11.013. Epub 2024 Dec 26.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that results in motor, sensory, cognitive, and affective deficits. Hippocampal demyelination, a common occurrence in MS, is linked to impaired cognitive function and mood. Despite this, the precise mechanisms underlying cognitive impairments in MS remain elusive. Pleiotrophin (PTN), secreted by neural stem cells and astrocytes, plays a crucial role in regulating cognition. This study investigates the role of astrocyte-derived PTN. We found that genetic deletion of astrocyte-derived PTN hinders hippocampal neurogenesis. Additionally, conditional ablation of PTN in astrocytes exacerbates neurogenic deficits in the demyelinated hippocampus. Importantly, overexpression of PTN in astrocytes reverses neurogenic and cognitive impairments caused by demyelination, underscoring PTN's protective role in MS. PTN cooperates with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) or anaplastic lymphoma kinase (ALK) receptors to activate the AKT signaling pathway, thereby enhancing hippocampal neurogenesis and cognition in demyelinated mice. These findings illuminate novel effects of astrocyte-derived PTN on hippocampal neurogenesis and cognition.
多发性硬化症（MS）是一种自身免疫性炎症性脱髓鞘疾病，会导致运动、感觉、认知和情感功能障碍。海马体脱髓鞘是MS中的常见现象，与认知功能和情绪受损有关。尽管如此，MS中认知障碍的具体机制仍不清楚。多效生长因子（PTN）由神经干细胞和星形胶质细胞分泌，在调节认知方面起着关键作用。本研究调查星形胶质细胞衍生的PTN的作用。我们发现，星形胶质细胞衍生的PTN基因缺失会阻碍海马体神经发生。此外，星形胶质细胞中PTN的条件性消融会加剧脱髓鞘海马体中的神经发生缺陷。重要的是，星形胶质细胞中PTN的过表达可逆转由脱髓鞘引起的神经发生和认知障碍，强调了PTN在MS中的保护作用。PTN与蛋白酪氨酸磷酸酶受体Z1型（PTPRZ1）或间变性淋巴瘤激酶（ALK）受体协同作用，激活AKT信号通路，从而增强脱髓鞘小鼠的海马体神经发生和认知能力。这些发现揭示了星形胶质细胞衍生的PTN对海马体神经发生和认知的新作用。
