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

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.

SUBMITTER: Phinney DG

PROVIDER: S-EPMC4598952 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Phinney Donald G DG Di Giuseppe Michelangelo M Njah Joel J Sala Ernest E Shiva Sruti S St Croix Claudette M CM Stolz Donna B DB Watkins Simon C SC Di Y Peter YP Leikauf George D GD Kolls Jay J Riches David W H DW Deiuliis Giuseppe G Kaminski Naftali N Boregowda Siddaraju V SV McKenna David H DH Ortiz Luis A LA

Nature communications 20151007

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 ...[more]

PMID: 26442449

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Project description:BackgroundHuman mesenchymal stem cells (MSCs) are therapeutic for clinical applications because of their excellent immunomodulatory and multiple lineage differentiation abilities at tissue injury sites. However, insufficient number of cells and lack of regenerative properties during in vitro expansion still limit the clinical applicability of MSC therapies. Here, we demonstrated a preconditioning strategy with trophoblast stem cell-derived extracellular vesicles (TSC-EVs) to boost the proliferation and regenerative capacity of MSCs.MethodsWe employed cell proliferation analyses such as CCK8 and BrdU assays to determine the proliferation-promoting role of TSC-EVs on MSCs. Osteogenic effects of TSC-EVs on MSCs were assessed by alkaline phosphatase (ALP) activity, calcium assays, and calvarial bone defect animal models. For skin regenerative effects, skin wound mice model was exploited to analyze wound-healing rate in this study, as well as immunofluorescence and histological staining evaluates. We also performed the small RNA profiling and RNA-sequencing analyzes to understand the cellular mechanism of TSC-EVs on MSCs.ResultsTSC-EVs significantly promoted MSC proliferation under xeno-free conditions and facilitated the therapeutic effects of MSCs, including osteogenesis, anti-senescence, and wound healing. Transcriptomic analysis also provided evidence that specific microRNAs in TSC-EVs and differentially expressed genes (DEGs) in TSC-EV-treated MSCs showed the possibility of TSC-EVs triggering the regenerative abilities of MSCs with cytokine interaction. Hence, we found that NGF/Akt signaling mediated the regenerative effects of TSC-EVs on MSCs as a particular cellular signaling pathway.ConclusionThe results of this study demonstrated the functional properties of TSC-EVs on MSCs for MSC-based therapeutic applications, suggesting that TSC-EVs may serve as a potential preconditioning source for MSC therapy in the clinical field of regenerative medicine.

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

Publications

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

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