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

Reported by Aviral Vatsa

Nat Commun. 2015 Oct 7;6:8472. doi: 10.1038/ncomms9472.

Phinney DG1, Di Giuseppe M2, Njah J2, Sala E3, Shiva S4, St Croix CM2,4,5, Stolz DB5, Watkins SC5, Di YP2, Leikauf GD2, Kolls J6, Riches DW7, Deiuliis G8,Kaminski N8, Boregowda SV1, McKenna DH9, Ortiz LA2.

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.

Author information

• 1Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
• 2Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
• 3Hospital Son Espases, Palma Mallorca 07010, Spain.
• 4Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
• 5Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
• 6Mellon Foundation Institute for Pediatric Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
• 7Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
• 8Department of Medicine, Yale University, New Haven, Connecticut 06510, USA.
• 9Department of Laboratory Medicine and Pathology, University of Minnesota, Saint Paul, Minnesota 55108, USA.

Gene regulation by dietary microRNAs

Reported by : Aviral Vatsa

Authors

Zempleni J1, Baier SR1, Howard KM1, Cui J2.

Can J Physiol Pharmacol. 2015 Apr 14:1-6. [Epub ahead of print]

PMID: 

26222444 (pubmed link)

Abstract

MicroRNAs (miRNAs) silence genes through destabilizing mRNA or preventing translation of mRNA, thereby playing an essential role in gene silencing. Traditionally, miRNAs have been considered endogenous regulators of genes, i.e., miRNAs synthesized by an organism regulate the genes in that organism. Recently, that dogma has been challenged in studies suggesting that food-borne miRNAs are bioavailable and affect gene expression in mice and humans. While the evidence in support of this theory may be considered weak for miRNAs that originate in plants, there is compelling evidence to suggest that humans use bovine miRNAs in cow's milk and avian miRNAs in chicken eggs for gene regulation. Importantly, evidence also suggests that mice fed a miRNA-depleted diet cannot compensate for dietary depletion by increased endogenous synthesis. Bioinformatics predictions implicate bovine miRNAs in the regulation of genes that play roles in human health and development. Current challenges in this area of research include that some miRNAs are unable to establish a cause-and-effect between miRNA depletion and disease in miRNA knockout mice, and sequence similarities and identities for bovine and human miRNAs render it difficult to distinguish between exogenous and endogenous miRNAs. Based on what is currently known about dietary miRNAs, the body of evidence appears to be sufficient to consider milk miRNA bioactive compounds in foods, and to increase research activities in this field.