Abstract
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.
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Acknowledgements
This work was supported by grants from University of Southern California (AMI funding to S.S), from International Science & Technology Cooperation Program of China (2015DFB30040 to S.S. and Y. Z), an Schoenleber Pilot Research Grant (to S.S) from University of Pennsylvania School of Dental Medicine, and National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services (R01DE017449 to S.S. and K99E025915 to C.C).
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D.L. designed and performed experiments, analyzed data and wrote the manuscript. C.C., X.K., S.L., Y.L., W.Y., R.Y., T.Y and R.W. performed experiments and analyzed data. S.S., and Y.Z. designed experiments, analyzed and interpreted data, wrote the manuscript and supervised the laboratory studies.
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Liu, D., Kou, X., Chen, C. et al. Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res 28, 918–933 (2018). https://doi.org/10.1038/s41422-018-0070-2
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DOI: https://doi.org/10.1038/s41422-018-0070-2
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