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Cited by 1,007Extracellular vesicles in diseaseMesenchymal stem cell researchAutophagy in Disease and Therapy

Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs

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Phinney, Donald G., Di Giuseppe, Michelangelo, Njah, Joel, Sala, Ernest, Shiva, Sruti, St Croix, Claudette M., Stolz, Donna B., Watkins, Simon C. +9 more·2015·Nature Communications
DOI 10.1038/ncomms9472PMC PMC4598952
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Abstract

Mesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs.

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  • MSCs secreted EVs encapsulating partially depolarized mitochondria, which were then engulfed by macrophages, resulting in enhanced macrophage bioenergetics and alleviated silicosis.

    “Phinney et al. reported that MSCs secreted EVs encapsulating partially depolarized Mt, which were then engulfed by macrophages, resulting in enhanced macrophage bioenergetics and alleviated silicosis [126].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [126]

    The Results sections on mitochondrial transfer and macrophage energetics report that MSC-derived microvesicles are engulfed by macrophages and that transferred, partially depolarized mitochondria enhance macrophage bioenergetics (pages not provided). A separate Results section reports that MSCs or MSC-derived exosomes reduced signs of silicosis in silica-exposed mice, but it does not establish that macrophage uptake of mitochondria or the resulting bioenergetic improvement caused that benefit. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • MSC-EVs may serve as effective carriers for transferring mitochondria, as their membranes can maintain the integrity and functional activity of mitochondria while increasing the lifespan of mitochondria in the bloodstream.

    “Recent findings have demonstrated that MSC-EVs may serve as effective carriers for transferring Mt, as their membranes can maintain the integrity and functional activity of Mt while increasing the lifespan of Mt in the bloodstream [123, 126, 128].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [126]

    The Results section ('MSCs package mitochondria in MVs for cellular transfer'; page unavailable) shows that MSCs package mitochondria into microvesicles for transfer. The Discussion reports improved macrophage bioenergetics after transfer. Neither passage establishes that vesicle membranes preserve mitochondrial integrity or function, or extend mitochondrial lifespan in the bloodstream; the reported persistence of mitochondrial material is in mouse lung tissue, not blood. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MSCs can also transfer mitochondria to immune cells.

    “MSCs can also transfer Mt to immune cells [126, 127].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [126]

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Authors
Phinney, D. G., Di Giuseppe, M., Njah, J., Sala, E., Shiva, S., St Croix, C. M., Stolz, D. B., Watkins, S. C., Di, Y. P., Leikauf, G. D., Kolls, J., Riches, D. W. H., Deiuliis, G., Kaminski, N., Boregowda, S. V., McKenna, D. H., & Ortiz, L. A.
Affiliations
  • Scripps Research Institute (US)
  • University of Pittsburgh (US)
  • Hospital Universitario Son Espases (ES)
  • National Jewish Health (US)
  • Yale University (US)
  • University of Minnesota (US)
Corresponding author
Ortiz, Luis A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2015-10-07
Volume
6
Issue
1
Pages
8472-8472
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms9472
PMC
PMC4598952
OpenAlex
W2204697639
Cited by
1,007
References
7
Citations by year
2026: 90 · 2025: 96 · 2024: 110 · 2023: 112 · 2022: 103 · 2021: 123 · 2020: 115 · 2019: 77 · 2018: 74 · 2017: 76 · 2016: 28 · 2015: 3
FWCI
26.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Docusalut (Conselleria de Salut i Consum del Govern de les Illes Balears) (submittedVersion, cc-by)
  • Hispana (submittedVersion, cc-by)
Funders
  • University of Minnesota
  • National Institutes of Health (R24OD018254, OD018254)
  • U.S. Public Health Service (HHSN268201000008C)
  • National Heart, Lung, and Blood Institute (R01HL071953, R01HL110334, R01HL114795, HHSN268201000008C, R01HL110344, R01HL091938)
  • National Cancer Institute (P30CA077598)
  • National Institute of Environmental Health Sciences (R01ES010859)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mesenchymal stem cells, mitophagy, extracellular vesicles, microvesicles, exosomes, microRNA, macrophages, mitochondrial depolarization, oxidative stress, vesicle fusion, Toll-like receptor signaling, macrophage activation, stem cell niche, immunomodulation, bioenergetics
MeSH terms
Extracellular Vesicles, Animals, Flow Cytometry, Humans, Macrophages, Microscopy, Electron, Mitochondria, Receptors, Immunologic, Silicosis, Blotting, Western, Signal Transduction, Oxidative Stress, Arrestins, MicroRNAs, Toll-Like Receptors, Toll-Like Receptor 4, Toll-Like Receptor 9, Mice, Myeloid Differentiation Factor 88, Cell-Derived Microparticles, Exosomes, Mesenchymal Stem Cells, Mitophagy

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