Mesenchymal stromal cell (MSC) therapy has regenerative potentials to treat various pathological conditions including neurological diseases. MSCs isolated from various organs can differentiate into specific cell types to repair organ damages. However, their paracrine mechanisms are predicted to predominantly mediate their immunomodulatory, pro-angiogenic, and regenerative properties. While preclinical studies highlight the significant potential of MSC therapy in mitigating neurological damage from stroke and traumatic brain injury, the variability in clinical trial outcomes may stem from the inherent heterogeneity of somatic MSCs. Accumulating evidence has demonstrated that induced pluripotent stem cells (iPSCs) are an ideal alternative resource for the unlimited expansion and biomanufacturing of MSCs. Thus, we investigated how iPSC-derived MSCs (iMSCs) influence properties of iPSC-derived neurons. Our findings demonstrate that the secretome from iMSCs possesses neurotrophic effects, improving neuronal survival and promoting neuronal outgrowth and synaptic activity in vitro Additionally, the iMSCs enhance metabolic activity via mitochondrial respiration in neurons, both in vitro and in mouse models. Glycolytic pathways also increased following the administration of iMSC secretome to iPSC-derived neurons. Consistently, in vivo experiments showed that intravenous administration of iMSCs compensated for the elevated energetic demand in male mice with irradiation-induced brain injury by restoring synaptic metabolic activity during acute brain damage. 18F-FDG PET imaging also detected an increase in brain glucose uptake following iMSC administration. Together, our results highlight the potential of iMSC-based therapy in treating neuronal damage in various neurological disorders, while paving the way for future research and potential clinical applications of iMSCs in regenerative medicine.Significance Statement Regenerative biotherapeutics using MSCs have emerged as a promising intervention for treating various neurological diseases. Our study explored the potential beneficial effects of human iPSC-derived MSCs (iMSCs) on neurons. We demonstrated that molecules secreted into the culture medium by iMSCs enhance regenerative capabilities by improving neuronal survival, growth, and metabolic activity, as well as synaptic functions, in human iPSC-derived neurons. Mouse experiments also suggested the potential of iMSC therapy to mitigate synaptic mitochondrial dysfunction and enhance brain glucose uptake during acute radiation-induced brain injury, steps that contribute to restoring normal neuronal function. Our results highlight that iMSCs may be a promising alternative cell product for treating neuronal damage, overcoming the inconsistent efficacy of somatic MSCs due to cell variability.

中文翻译：

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人 iPSC 来源的 MSC 在急性神经元损伤模型中诱导神经营养效应并改善代谢活性。


间充质基质细胞 （MSC） 疗法具有治疗各种病理状况（包括神经系统疾病）的再生潜力。从各种器官中分离的 MSC 可以分化成特定的细胞类型来修复器官损伤。然而，预计它们的旁分泌机制主要介导其免疫调节、促血管生成和再生特性。虽然临床前研究强调了 MSC 疗法在减轻中风和创伤性脑损伤造成的神经损伤方面的巨大潜力，但临床试验结果的可变性可能源于体细胞 MSC 固有的异质性。越来越多的证据表明，诱导多能干细胞 （iPSC） 是 MSC 无限扩增和生物制造的理想替代资源。因此，我们研究了 iPSC 衍生的 MSC （iMSC） 如何影响 iPSC 衍生的神经元的特性。我们的研究结果表明，来自 iMSC 的分泌组具有神经营养作用，在体外提高神经元存活并促进神经元生长和突触活性此外，iMSC 在体外和小鼠模型中通过神经元中的线粒体呼吸增强代谢活性。将 iMSC 分泌蛋白组施用于 iPSC 衍生的神经元后，糖酵解途径也增加。一致的体内实验表明，静脉内施用 iMSC 通过恢复急性脑损伤期间的突触代谢活动来补偿照射诱导脑损伤雄性小鼠的能量需求增加。18F-FDG PET 成像还检测到 iMSC 给药后脑葡萄糖摄取增加。 总之，我们的结果强调了基于 iMSC 的疗法在治疗各种神经系统疾病中的神经元损伤方面的潜力，同时为 iMSC 在再生医学中的未来研究和潜在临床应用铺平了道路。意义声明 使用 MSC 的再生生物治疗已成为治疗各种神经系统疾病的一种有前途的干预措施。我们的研究探讨了人类 iPSC 衍生的 MSC （iMSC） 对神经元的潜在有益影响。我们证明，iMSC 分泌到培养基中的分子通过改善人类 iPSC 来源神经元的神经元存活、生长和代谢活动以及突触功能来增强再生能力。小鼠实验还表明，iMSC 疗法有可能减轻突触线粒体功能障碍并增强急性辐射诱导脑损伤期间的脑葡萄糖摄取，这些步骤有助于恢复正常的神经元功能。我们的结果强调，iMSCs 可能是一种很有前途的治疗神经元损伤的替代细胞产品，克服了由于细胞变异性而导致的体细胞 MSCs 疗效不一致的问题。