Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China; Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China.
Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China.
Mol Ther. 2023 May 3;31(5):1293-1312. doi: 10.1016/j.ymthe.2023.02.004. Epub 2023 Feb 9.
Factors released from the nervous system always play crucial roles in modulating bone metabolism and regeneration. How the brain-driven endocrine axes maintain bone homeostasis, especially under metabolic disorders, remains obscure. Here, we found that neural stem cells (NSCs) residing in the subventricular zone participated in lipid metabolism homeostasis of regenerative bone through exosomal perilipin 5 (PLIN5). Fluorescence-labeled exosomes tracing and histological detection identified that NSC-derived exosomes (NSC-Exo) could travel from the lateral ventricle into bone injury sites. Homocysteine (Hcy) led to osteogenic and angiogenic impairment, whereas the NSC-Exo were confirmed to restore it. Mecobalamin, a clinically used neurotrophic drug, further enhanced the protective effects of NSC-Exo through increased PLIN5 expression. Mechanistically, NSC-derived PLIN5 reversed excessive Hcy-induced lipid metabolic imbalance and aberrant lipid droplet accumulation through lipophagy-dependent intracellular lipolysis. Intracerebroventricular administration of mecobalamin and/or AAV-shPlin5 confirmed the effects of PLIN5-driven endocrine modulations on new bone formation and vascular reconstruction in hyperhomocysteinemic and high-fat diet models. This study uncovered a novel brain-skeleton axis that NSCs in the mammalian brain modulated bone regeneration through PLIN5-driven lipid metabolism modulation, providing evidence for lipid- or bone-targeted medicine development.
神经系统释放的因子在调节骨代谢和再生中始终起着至关重要的作用。大脑驱动的内分泌轴如何维持骨稳态，特别是在代谢紊乱的情况下，仍然不清楚。在这里，我们发现位于侧脑室的神经干细胞（NSC）通过细胞外体 perilipin 5（PLIN5）参与再生骨的脂质代谢稳态。荧光标记的外体追踪和组织学检测表明，NSC 衍生的外体（NSC-Exo）可以从侧脑室迁移到骨损伤部位。同型半胱氨酸（Hcy）导致成骨和血管生成损伤，而 NSC-Exo 被证实可以恢复它。甲钴胺，一种临床使用的神经营养药物，通过增加 PLIN5 的表达进一步增强了 NSC-Exo 的保护作用。在机制上，NSC 衍生的 PLIN5 通过脂噬依赖性细胞内脂肪分解来逆转过量 Hcy 诱导的脂质代谢失衡和异常脂质滴积累。脑室内给予甲钴胺和/或 AAV-shPlin5 证实了 PLIN5 驱动的内分泌调节对高同型半胱氨酸血症和高脂肪饮食模型中新骨形成和血管重建的影响。这项研究揭示了一个新的脑-骨轴，哺乳动物大脑中的 NSCs 通过 PLIN5 驱动的脂质代谢调节来调节骨再生，为脂质或骨靶向药物的开发提供了证据。
