Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs
By D. Phinney, Michelangelo Di Giuseppe, Joel Njah, E. Sala, S. Shiva, C. S. St Croix, D. Stolz, Simon C Watkins, Y. Di, George D. Leikauf and 7 more. Nature Communications, 2015
924 citations recorded by the source corpus.
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. The physiological role of crosstalk between mesenchymal stem cells (MSC) and macrophages is unclear. Here, Phinney et al. show that MSCs transfer mitochondria to macrophages under oxidative stress, and desensitize macrophages to mitochondria by using microvesicles to repress Toll receptor signalling.
Subfields: Cancer Research, Epidemiology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/42590f97dc8b507499fade85e4fe062a0abaf0af
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Citations in the corpus
- Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer (2017, neutral): “Most normal cells respond to oxidative stress, hypoxia, DNA-damaging agents, and/or nutrient deprivation by undergoing autophagy, apoptosis, and senescence (48).”
- Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer (2017, background): “Phinney et al previously showed that MSCs donate their mitochondria to human macrophages under oxidative stress via EV-mediated transport thereby enhancing their bioenergetics((24)).”
- Extracellular Vesicles: Unique Intercellular Delivery Vehicles. (2017, background): “Conversely, EV transfer of miRNAs from MSCs to macrophages suppresses the macrophage immune response by altering NFkB signaling and downstream reduction of TLR (MyD88-dependent) pattern recognition [80].”