Endocrine modulation of brain-skeleton axis driven by neural stem cell-derived perilipin 5 in the lipid metabolism homeostasis for bone regeneration

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 subven-tricular zone participated in lipid metabolism homeostasis of regenerative bone through exosomal perilipin 5 (PLIN5). Fluo-rescence-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 clin-ically used neurotrophic drug, further enhanced the protective effects of NSC-Exo through increased PLIN5 expression. Mech-anistically, NSC-derived PLIN5 reversed excessive Hcy-induced lipid metabolic imbalance and aberrant lipid droplet accumu-lation through lipophagy-dependent intracellular lipolysis. Intracerebroventricular administration of mecobalamin and/ or AAV-shPlin5 confirmed the effects of PLIN5-driven endo-crine modulations on new bone formation and vascular recon-struction 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 evi-dence for lipid-or bone-targeted medicine development.