Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 3E1, Canada.
Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada.
Int J Mol Sci. 2024 Jun 14;25(12):6549. doi: 10.3390/ijms25126549.
Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain. pNSCs are quiescent under baseline conditions and can be activated upon injury. Herein, we asked whether human pNSCs and dNSCs can be isolated during the maturation of human cerebral organoids (COs) and activated by drugs known to regulate mouse NSC behavior. We demonstrate that self-renewing, multipotent pNSC and dNSC populations are present in human COs and express genes previously characterized in mouse NSCs. The drug NWL283, an inhibitor of apoptosis, reduced cell death in COs but did not improve NSC survival. Metformin, a drug used to treat type II diabetes that is known to promote NSC activation in mice, was found to expand human NSC pools. Together, these findings are the first to identify and characterize human pNSCs, advancing our understanding of the human NSC lineage and highlighting drugs that enhance their activity.
神经干细胞（NSCs）的激活与损伤小鼠模型中功能改善相关。在小鼠大脑中，NSCs 已经得到了广泛的研究，包括（1）原始 NSCs（pNSCs）和（2）定型 NSCs（dNSCs）。pNSCs 是 NSC 谱系中的最早细胞，在胚胎和成年小鼠大脑中产生 dNSCs。pNSCs 在基线条件下处于静止状态，可在损伤时被激活。在此，我们想知道在人类类器官（COs）的成熟过程中是否可以分离人类 pNSCs 和 dNSCs，并通过已知可调节小鼠 NSC 行为的药物来激活它们。我们证明了具有自我更新能力和多能性的 pNSC 和 dNSC 群体存在于人类 COs 中，并表达了先前在小鼠 NSCs 中鉴定出的基因。凋亡抑制剂 NWL283 可减少 COs 中的细胞死亡，但不能提高 NSC 的存活率。二甲双胍是一种用于治疗 II 型糖尿病的药物，已知可促进小鼠 NSC 的激活，我们发现它可扩增人类 NSC 池。总之，这些发现首次鉴定和表征了人类 pNSCs，增进了我们对人类 NSC 谱系的理解，并强调了增强其活性的药物。
