Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation

• Published in: Nature communications Vol. 15; no. 1; pp. 7855 - 24
• Main Authors: Wang, Jiayi, Zhao, Mengke, Wang, Meina, Fu, Dong, Kang, Lin, Xu, Yu, Shen, Liming, Jin, Shilin, Wang, Liang, Liu, Jing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/2; 14/19; 631/532/2182; 631/61; 631/80/642/333; Adenosine Triphosphate - metabolism; Biomimetics; Cell Differentiation; Cell therapy; Central nervous system; Electron transport; Heterogeneity; Homeostasis; Humanities and Social Sciences; Humans; Medical treatment; Membranes; Mitochondria; Mitochondria - metabolism; multidisciplinary; Nervous system; Neural stem cells; Neural Stem Cells - metabolism; Neurological diseases; Organelles; Organelles - metabolism; Oxidative Phosphorylation; Phosphorylation; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Self-assembly; Stem cells; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52171-2

Oxidative phosphorylation (OXPHOS) in the mitochondrial inner membrane is a therapeutic target in many diseases. Neural stem cells (NSCs) show progress in improving mitochondrial dysfunction in the central nervous system (CNS). However, translating neural stem cell-based therapies to the clinic is challenged by uncontrollable biological variability or heterogeneity, hindering uniform clinical safety and efficacy evaluations. We propose a systematic top-down design based on membrane self-assembly to develop neural stem cell-derived oxidative phosphorylating artificial organelles (SAOs) for targeting the central nervous system as an alternative to NSCs. We construct human conditionally immortal clone neural stem cells (iNSCs) as parent cells and use a streamlined closed operation system to prepare neural stem cell-derived highly homogenous oxidative phosphorylating artificial organelles. These artificial organelles act as biomimetic organelles to mimic respiration chain function and perform oxidative phosphorylation, thus improving ATP synthesis deficiency and rectifying excessive mitochondrial reactive oxygen species production. Conclusively, we provide a framework for a generalizable manufacturing procedure that opens promising prospects for disease treatment. Regulating oxidative phosphorylation and restoring redox homeostasis are crucial in neurological disorders. Here, the authors develop a top-down membrane self-assembly strategy to develop stem cell-derived artificial organelles (SAOs) that mimic mitochondrial oxidative phosphorylation without the risks associated with stem cell therapy.