Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer
Open accessAbstract
Rationale: Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs’ effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer. Objectives: To determine the effects of human MSCs on macrophage function in the ARDS environment and to elucidate the mechanisms of these effects. Methods: Human monocyte–derived macrophages (MDMs) were studied in noncontact coculture with human MSCs when stimulated with LPS or bronchoalveolar lavage fluid (BALF) from patients with ARDS. Murine alveolar macrophages (AMs) were cultured ex vivo with/without human MSC-derived EVs before adoptive transfer to LPS-injured mice. Measurements and Main Results: MSCs suppressed cytokine production, increased M2 macrophage marker expression, and augmented phagocytic capacity of human MDMs stimulated with LPS or ARDS BALF. These effects were partially mediated by CD44-expressing EVs. Adoptive transfer of AMs pretreated with MSC-derived EVs reduced inflammation and lung injury in LPS-injured mice. Inhibition of oxidative phosphorylation in MDMs prevented the modulatory effects of MSCs. Generating dysfunctional mitochondria in MSCs using rhodamine 6G pretreatment also abrogated these effects. Conclusions: In the ARDS environment, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer. MSC-induced changes in macrophage phenotype critically depend on enhancement of macrophage oxidative phosphorylation. AMs treated with MSC-derived EVs ameliorate lung injury in vivo.
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MSCs alleviated LPS-induced lung injury by transferring functional mitochondria to macrophages via EVs, which reprogrammed them from an M1 to an M2 phenotype.
“Morrison et al. demonstrated that MSCs alleviated LPS-induced lung injury by transferring functional Mt to macrophages via EVs, which reprogrammed them from an M1 to an M2 phenotype [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 [128]
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 [128]
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“In addition, Morrison et al. demonstrated that MSCs alleviated LPS-induced lung injury by transferring functional Mt to macrophages via EVs, which reprogrammed them from an M1 to an M2 phenotype [128].”
- Authors
- Morrison, T. J., Jackson, M. V., Cunningham, E. K., Kissenpfennig, A., McAuley, D. F., O’Kane, C. M., & Krasnodembskaya, A. D.
- Affiliations
- Queen's University Belfast (GB)
- Corresponding author
- Krasnodembskaya, Anna D.
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-11
- Volume
- 196
- Issue
- 10
- Pages
- 1275-1286
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC5694830
- OpenAlex
- W2623687009
- Cited by
- 796
- References
- 7
- Citations by year
- 2026: 69 · 2025: 77 · 2024: 113 · 2023: 101 · 2022: 119 · 2021: 119 · 2020: 103 · 2019: 50 · 2018: 34 · 2017: 10
- FWCI
- 31.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (publishedVersion, other-oa)
- Funders
- Department for Employment and Learning, Northern Ireland
- Public Health Agency (SPI/5299/16)
- National Institutes of Health
- Medical Research Council (MR/M009149/1, MR/L017229/1)
- National Center for Research Resources (P40RR017447)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Keywords
- mesenchymal stem cells, acute respiratory distress syndrome, lung injury, macrophage polarization, extracellular vesicles, mitochondrial transfer, M2 macrophages, oxidative phosphorylation, CD44, alveolar macrophages, phagocytosis, cell therapy, paracrine signaling, lipopolysaccharide, bronchoalveolar lavage fluid
- MeSH terms
- Extracellular Vesicles, Animals, Female, Humans, Male, Mitochondria, Macrophage-Activating Factors, Models, Animal, Mesenchymal Stem Cell Transplantation, Mice, Acute Lung Injury, Mesenchymal Stem Cells
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