Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors

摘要

In the human body,50-70 billion cells die every day,resulting in the generation of a large number of apoptotic bodies.However,the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear.In this study,we used Fasdeficient MRL/Ipr and Caspase 3-/-mice to show that reduction of apoptotic body formation significantly impaired the self-renewal and osteo-/adipo-genic differentiation of bone marrow mesenchymal stem cells (MSCs).Systemic infusion of exogenous apoptotic bodies rescued the MSC impairment and also ameliorated the osteopenia phenotype in MRL/Ipr,Caspase 3-/-and ovariectomized (OVX) mice.Mechanistically,we showed that MSCs were able to engulf apoptotic bodies via integrin avβ3 and reuse apoptotic body-derived ubiquitin ligase RNF146 and miR-328-3p to inhibit Axin1 and thereby activate the Wnt/β-catenin pathway.Moreover,we used a parabiosis mouse model to reveal that apoptotic bodies participated in the circulation to regulate distant MSCs.This study identifies a previously unknown role of apoptotic bodies in maintaining MSC and bone homeostasis in both physiological and pathological contexts and implies the potential use of apoptotic bodies to treat osteoporosis.