title: 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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Di Giuseppe
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Njah
authors.affiliation: Hospital Son Espases, Palma Mallorca 07010, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Sala
authors.affiliation: Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.|Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.|Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Y Peter
authors.initials: YP
authors.lastname: Di
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.affiliation: Mellon Foundation Institute for Pediatric Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Kolls
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.affiliation: Department of Medicine, Yale University, New Haven, Connecticut 06510, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Deiuliis
authors.affiliation: Department of Medicine, Yale University, New Haven, Connecticut 06510, USA.
authors.forename: Naftali
authors.identifier: http://orcid.org/0000-0001-5917-4601
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Siddaraju V
authors.initials: SV
authors.lastname: Boregowda
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Saint Paul, Minnesota 55108, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: McKenna
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Ortiz
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D015153:Blotting, Western; D055252:Cell-Derived Microparticles / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D018384:Oxidative Stress; D011971:Receptors, Immunologic / Q000235:genetics; D015398:Signal Transduction; D012829:Silicosis / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D019390:Arrestins; C092228:Marco protein, mouse; D035683:MicroRNAs; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors