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Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury

Abstract

Bone marrow–derived stromal cells (BMSCs) protect against acute lung injury (ALI). To determine the role of BMSC mitochondria in this protection, we airway-instilled mice first with lipopolysaccharide (LPS) and then with either mouse BMSCs (mBMSCs) or human BMSCs (hBMSCs). Live optical studies revealed that the mBMSCs formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the alveolar epithelia in these mice, releasing mitochondria-containing microvesicles that the epithelia engulfed. The presence of BMSC-derived mitochondria in the epithelia was evident optically, as well as by the presence of human mitochondrial DNA in mouse lungs instilled with hBMSCs. The mitochondrial transfer resulted in increased alveolar ATP concentrations. LPS-induced ALI, as indicated by alveolar leukocytosis and protein leak, inhibition of surfactant secretion and high mortality, was markedly abrogated by the instillation of wild-type mBMSCs but not of mutant, GJC-incompetent mBMSCs or mBMSCs with dysfunctional mitochondria. This is the first evidence, to our knowledge, that BMSCs protect against ALI by restituting alveolar bioenergetics through Cx43-dependent alveolar attachment and mitochondrial transfer.

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Figure 1: mBMSCs in live alveoli.
Figure 2: Cx43 expression in mBMSCs and alveoli.
Figure 3: Responses of alveolus-attached mBMSCs 4–8 h after LPS instillation.
Figure 4: Mitochondrial transfer from BMSCs 24 h after LPS instillation.
Figure 5: Effect of mBMSCs on alveolar bioenergetics.
Figure 6: Effect of mBMSCs on injury outcomes.

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Acknowledgements

This study was supported by US National Institutes of Health grants HL64896, HL36024 and HL57556 to J.B. The authors thank G. Yellen (Harvard University) for the Perceval plasmid.

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Authors and Affiliations

Authors

Contributions

M.N.I. carried out the experiments, prepared the figures and wrote the initial manuscript. S.R.D. carried out the protein gel assays. M.T.E. contributed to the flow cytometry experiments. M.W. carried out the RNA isolation and RT-PCR experiments. L.S. and S.K.Q. carried out the plasmid amplifications and BMSC transfections. K.W. contributed to the epithelial cell isolation experiments. D.J.R. contributed to the imaging experiments. S.B. contributed to the experimental design. J.B. was responsible for the overall project and wrote the initial manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Jahar Bhattacharya.

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The authors declare no competing financial interests.

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Islam, M., Das, S., Emin, M. et al. Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 18, 759–765 (2012). https://doi.org/10.1038/nm.2736

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