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

Nature Medicine volume 18, pages 759–765 (2012)Cite this article

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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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References

  1. Prockop, D.J., Kota, D.J., Bazhanov, N. & Reger, R.L. Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs). J. Cell Mol Med. 14, 2190–2199 (2010).

    Article  Google Scholar 

  2. Parekkadan, B. & Milwid, J.M. Mesenchymal stem cells as therapeutics. Annu. Rev. Biomed. Eng. 12, 87–117 (2010).

    Article  CAS  Google Scholar 

  3. Weiss, D.J., Kolls, J.K., Ortiz, L.A., Panoskaltsis-Mortari, A. & Prockop, D.J. Stem cells and cell therapies in lung biology and lung diseases. Proc. Am. Thorac. Soc. 5, 637–667 (2008).

    Article  Google Scholar 

  4. Matthay, M.A., Goolaerts, A., Howard, J.P. & Lee, J.W. Mesenchymal stem cells for acute lung injury: preclinical evidence. Crit. Care Med. 38, S569–S573 (2010).

    Article  Google Scholar 

  5. Rubenfeld, G.D. et al. Incidence and outcomes of acute lung injury. N. Engl. J. Med. 353, 1685–1693 (2005).

    Article  CAS  Google Scholar 

  6. Krause, D.S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).

    Article  CAS  Google Scholar 

  7. Ortiz, L.A. et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc. Natl. Acad. Sci. USA 100, 8407–8411 (2003).

    Article  CAS  Google Scholar 

  8. Chang, J.C., Summer, R., Sun, X., Fitzsimmons, K. & Fine, A. Evidence that bone marrow cells do not contribute to the alveolar epithelium. Am. J. Respir. Cell Mol. Biol. 33, 335–342 (2005).

    Article  CAS  Google Scholar 

  9. Kotton, D.N., Fabian, A.J. & Mulligan, R.C. Failure of bone marrow to reconstitute lung epithelium. Am. J. Respir. Cell Mol. Biol. 33, 328–334 (2005).

    Article  CAS  Google Scholar 

  10. Lee, J.W., Fang, X., Gupta, N., Serikov, V. & Matthay, M.A. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc. Natl. Acad. Sci. USA 106, 16357–16362 (2009).

    Article  CAS  Google Scholar 

  11. Gupta, N. et al. Intrapulmonary delivery of bone marrow–derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J. Immunol. 179, 1855–1863 (2007).

    Article  CAS  Google Scholar 

  12. Curley, G.F. et al. Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax published online, doi:10.1136/thoraxjnl-2011-201059 (2011).

  13. Mei, S.H. et al. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 4, e269 (2007).

    Article  Google Scholar 

  14. Xu, J. et al. Mesenchymal stem cell-based angiopoietin-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice. J. Pathol. 214, 472–481 (2008).

    Article  CAS  Google Scholar 

  15. Ortiz, L.A. et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc. Natl. Acad. Sci. USA 104, 11002–11007 (2007).

    Article  CAS  Google Scholar 

  16. Németh, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42–49 (2009).

    Article  Google Scholar 

  17. Dada, L.A. & Sznajder, J.I. Mitochondrial Ca2+ and ROS take center stage to orchestrate TNF-α–mediated inflammatory responses. J. Clin. Invest. 121, 1683–1685 (2011).

    Article  CAS  Google Scholar 

  18. Harrois, A., Huet, O. & Duranteau, J. Alterations of mitochondrial function in sepsis and critical illness. Curr. Opin. Anaesthesiol. 22, 143–149 (2009).

    Article  Google Scholar 

  19. Brealey, D. et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360, 219–223 (2002).

    Article  CAS  Google Scholar 

  20. Otsu, K. et al. Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood 113, 4197–4205 (2009).

    Article  CAS  Google Scholar 

  21. Spees, J.L., Olson, S.D., Whitney, M.J. & Prockop, D.J. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl. Acad. Sci. USA 103, 1283–1288 (2006).

    Article  CAS  Google Scholar 

  22. Plotnikov, E.Y. et al. Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J. Cell Mol Med. 12, 1622–1631 (2008).

    Article  CAS  Google Scholar 

  23. Parthasarathi, K. et al. Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries. J. Clin. Invest. 116, 2193–2200 (2006).

    Article  CAS  Google Scholar 

  24. Lindert, J., Perlman, C.E., Parthasarathi, K. & Bhattacharya, J. Chloride-dependent secretion of alveolar wall liquid determined by optical-sectioning microscopy. Am. J. Respir. Cell Mol. Biol. 36, 688–696 (2007).

    Article  CAS  Google Scholar 

  25. Hawat, G., Benderdour, M., Rousseau, G. & Baroudi, G. Connexin 43 mimetic peptide Gap26 confers protection to intact heart against myocardial ischemia injury. Pflugers Arch. 460, 583–592 (2010).

    Article  CAS  Google Scholar 

  26. Beahm, D.L. et al. Mutation of a conserved threonine in the third transmembrane helix of α- and β-connexins creates a dominant-negative closed gap junction channel. J. Biol. Chem. 281, 7994–8009 (2006).

    Article  CAS  Google Scholar 

  27. Corti, M., Brody, A.R. & Harrison, J.H. Isolation and primary culture of murine alveolar type II cells. Am. J. Respir. Cell Mol. Biol. 14, 309–315 (1996).

    Article  CAS  Google Scholar 

  28. Das Sarma, J. et al. Multimeric connexin interactions prior to the trans-Golgi network. J. Cell Sci. 114, 4013–4024 (2001).

    CAS  Google Scholar 

  29. Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H.H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).

    Article  CAS  Google Scholar 

  30. Rowlands, D.J. et al. Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels. J. Clin. Invest. 121, 1986–1999 (2011).

    Article  CAS  Google Scholar 

  31. Macia, E. et al. Dynasore, a cell-permeable inhibitor of dynamin. Dev. Cell 10, 839–850 (2006).

    Article  CAS  Google Scholar 

  32. Heller, A.R. et al. Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung. Eur. J. Anaesthesiol. 24, 258–266 (2007).

    Article  CAS  Google Scholar 

  33. Kao, S.J., Liu, D.D., Su, C.F. & Chen, H.I. Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin. J. Cardiovasc. Pharmacol. 50, 333–342 (2007).

    Article  CAS  Google Scholar 

  34. Guzy, R.D. et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 1, 401–408 (2005).

    Article  CAS  Google Scholar 

  35. Berg, J., Hung, Y.P. & Yellen, G. A genetically encoded fluorescent reporter of ATP:ADP ratio. Nat. Methods 6, 161–166 (2009).

    Article  CAS  Google Scholar 

  36. Ashino, Y., Ying, X., Dobbs, L.G. & Bhattacharya, J. [Ca2+]i oscillations regulate type II cell exocytosis in the pulmonary alveolus. Am. J. Physiol. Lung Cell Mol. Physiol. 279, L5–L13 (2000).

    Article  CAS  Google Scholar 

  37. Wang, P.M., Ashino, Y., Ichimura, H. & Bhattacharya, J. Rapid alveolar liquid removal by a novel convective mechanism. Am. J. Physiol. Lung Cell Mol. Physiol. 281, L1327–L1334 (2001).

    Article  CAS  Google Scholar 

  38. Whitsett, J.A., Wert, S.E. & Weaver, T.E. Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu. Rev. Med. 61, 105–119 (2010).

    Article  CAS  Google Scholar 

  39. Dietl, P. & Haller, T. Exocytosis of lung surfactant: from the secretory vesicle to the air-liquid interface. Annu. Rev. Physiol. 67, 595–621 (2005).

    Article  CAS  Google Scholar 

  40. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    Article  CAS  Google Scholar 

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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

  1. Department of Medicine, Division of Pulmonary, Lung Biology Laboratory, Allergy and Critical Care Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA

    Mohammad Naimul Islam, Shonit R Das, Memet T Emin, Michelle Wei, Li Sun, Kristin Westphalen, David J Rowlands, Sadiqa K Quadri, Sunita Bhattacharya & Jahar Bhattacharya

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  1. Mohammad Naimul Islam
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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.

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Correspondence to Jahar Bhattacharya.

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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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