Journal Article

Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties

Ferrera, René, Institut National de la Santé et de la Recherche Médicale (INSERM), Manin, Sylvie, Plateforme de Cytométrie en Flux ; GHU A. Chenevier - Henri Mondor (Inserm U955, équipe 16), Motterlini, Roberto, Meningaud, Jean-Paul, da Silva, Claire Crola, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon) ; Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine) ; Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val

2017

Overview

Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms – activation of autophagy, HO-1 and mitochondrial biogenesis – occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo . Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK
• Subject: 13 / 13/100 / 13/2 / 13/31 / 14 / 14/1 / 14/34 / 38 / 38/77 / 631/443 / 631/80 / Acids - metabolism / Animals / Apoptosis / Apoptosis - drug effects / Biochemistry / Biomedical and Life Sciences / Biosynthesis / Cardiomyocytes / Cell Biology / Cell culture / Cell Cycle Analysis / Cell death / Coculture Techniques / Cytoprotection - drug effects / Doxorubicin - pharmacology / Endosomes - drug effects / Endosomes - metabolism / Endothelial cells / Enzyme Induction - drug effects / Heart diseases / Heme / Heme oxygenase (decyclizing) / Heme Oxygenase-1 - biosynthesis / Heme Oxygenase-1 - metabolism / Human Umbilical Vein Endothelial Cells - drug effects / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Ischemia / Life Sciences / Male / Mesenchymal Stem Cell Transplantation / Mesenchymal stem cells / Mesenchymal Stromal Cells - drug effects / Mesenchymal Stromal Cells - metabolism / Mesenchymal Stromal Cells - ultrastructure / Mesenchyme / Mice, Inbred C57BL / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - ultrastructure / Mitochondrial Degradation - drug effects / Myocardial infarction / Myocardial Infarction - metabolism / Myocardial Infarction - pathology / Organelles / Original Paper / Oxidative stress / Oxygenase / Phagocytosis / Reactive Oxygen Species - metabolism / Reperfusion / Rodents / Signal Transduction - drug effects / Somatic cells / Stem cell transplantation / Stem Cells