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

• Published in: Cell research Vol. 28; no. 9; pp. 918 - 933
• Main Authors: Liu, Dawei, Kou, Xiaoxing, Chen, Chider, Liu, Shiyu, Liu, Yao, Yu, Wenjing, Yu, Tingting, Yang, Ruili, Wang, Runci, Zhou, Yanheng, Shi, Songtao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 13/100; 13/2; 13/31; 13/51; 13/89; 14/19; 631/532/2074; 631/80/82/23; 64/110; 64/60; 82/80; Animals; Apoptosis; Biocompatibility; Biomedical and Life Sciences; Bone Diseases, Metabolic - metabolism; Bone Diseases, Metabolic - pathology; Bone marrow; Bone turnover; Caspase; Caspase-3; Cell Biology; Cell Differentiation; Cell Proliferation; Cell self-renewal; Extracellular Vesicles - metabolism; Female; Homeostasis; Life Sciences; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Osteopenia; Osteoporosis; Ovariectomy; Parabiosis; Phenotypes; Stem cell transplantation; Stem cells; Ubiquitin; Ubiquitin-protein ligase; Wnt protein; β-Catenin; Apoptotic Bodies; Population Doubling Rate; Marrow Mesenchymal Stem Cells (MSCs); Receptor Activator Of Nuclear Factor kappa-B Ligand (RANKL); Osteogenic Induction Conditions
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-018-0070-2

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 Fas-deficient MRL/ lpr 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/ lpr , Caspase 3 −/− and ovariectomized (OVX) mice. Mechanistically, we showed that MSCs were able to engulf apoptotic bodies via integrin αvβ3 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.