英国剑桥大学Stefano Pluchino和美国科罗拉多大学Angelo D’Alessandro共同合作，近期取得重要工作进展。他们研究提出，胆固醇合成增加促使多发性硬化症患者干细胞来源模型产生神经毒性。相关研究成果2024年10月21日在线发表于《细胞—干细胞》杂志上。

据介绍，在进行性多发性硬化症（PMS）患者的脑损伤中发现了衰老的神经祖细胞。然而，它们在疾病病理生物学中的作用和对病变环境的贡献尚不清楚。

通过从PMS患者成纤维细胞中建立直接诱导的神经干/祖细胞（iNSC）系，研究人员在体外研究了它们的衰老表型。衰老与炎症信号、高代谢和衰老相关分泌表型（SASP）密切相关。PMS来源的iNSC显示出葡萄糖依赖性脂肪酸和胆固醇合成增加，导致脂滴积聚。

研究发现3-羟基-3-甲基戊二酰（HMG）-辅酶A（CoA）还原酶（HMGCR）介导的脂肪生成状态，通过胆固醇依赖性转录因子在PMS iNSC中诱导SASP。PMS iNSC系的SASP在成熟神经元中诱导神经毒性，用HMGCR抑制剂辛伐他汀治疗改变了PMS iNSC-SASP，促进了细胞保护作用并降低了神经毒性。

总之，这一研究结果表明，PMS iNSC存在一种与疾病相关、与胆固醇相关、高代谢的表型，可导致神经毒性信号传导，并且在药理学上是可治愈的。

附：英文原文

Title: Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis

Author: Rosana-Bristena Ionescu, Alexandra M. Nicaise, Julie A. Reisz, Eleanor C. Williams, Pranathi Prasad, Cory M. Willis, Madalena B.C. Simes-Abade, Linda Sbarro, Monika Dzieciatkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti-Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D’Alessandro, Stefano Pluchino

Issue&Volume: 2024-10-21

Abstract: Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.

DOI: 10.1016/j.stem.2024.09.014

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00328-X