Highly Purified Human Extracellular Vesicles Produced by Stem Cells Alleviate Aging Cellular Phenotypes of Senescent Human Cells

Abstract

Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communications and exert various biological activities via delivering unique cargos of functional molecules such as RNAs and proteins to recipient cells. Previous studies showed that EVs produced and secreted by human mesenchymal stem cells (MSCs) can substitute intact MSCs for tissue repair and regeneration. In this study, we examined properties and functions of EVs from human induced pluripotent stem cells (iPSCs) that can be cultured infinitely under a chemically defined medium free of any exogenous EVs. We collected and purified EVs secreted by human iPSCs and MSCs. Purified EVs produced by both stem cell types have similar sizes (∼150 nm in diameter), but human iPSCs produced 16‐fold more EVs than MSCs. When highly purified iPSC‐EVs were applied in culture to senescent MSCs that have elevated reactive oxygen species (ROS), human iPSC‐EVs reduced cellular ROS levels and alleviated aging phenotypes of senescent MSCs. Our discovery reveals that EVs from human stem cells can alleviate cellular aging in culture, at least in part by delivering intracellular peroxiredoxin antioxidant enzymes. Stem Cells 2019;37:779–790

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

“…Since the pure isolation of different EV subpopulations according to their intracellular origin is not yet resolved, EVs are often categorized based on their size as small and large EVs . EVs transfer a wide array of biologically important molecules, such as proteins, lipids, mRNAs, and miRNAs in a concentrated form when they target the recipient cells, and the roles of mesenchymal stem cell‐derived and mesenchymal stromal cell‐derived EVs, for example, have already been intensively studied …”

“…6 EVs transfer a wide array of biologically important molecules, such as proteins, lipids, mRNAs, and miRNAs in a concentrated form when they target the recipient cells, 5,7 and the roles of mesenchymal stem cell-derived and mesenchymal stromal cell-derived EVs, for example, have already been intensively studied. 8,9 Despite the increasing knowledge how ISC niche is formed, not many studies have so far been published on the way of transmitting ISC niche factors. In a recent report, the short-range Wnt gradient among ISCs and Paneth cells has been visualized.…”

Tunneling nanotubes mediate the expression of senescence markers in mesenchymal stem/stromal cell spheroids

“…10 Compared with monodispersed cells, spheroid formation can further potentiate cell survival 11 and secretion of endogenous growth factors, 12 motivating continued investigation into the mechanism and therapeutic effects of cell-cell communication within a spheroid. This complex network of communication is orchestrated via signals from the microenvironment such as paracrine or autocrine-acting soluble factors 13 and intercellular communication through gap junctions, extracellular vesicles, 14 and tunneling nanotubes (TNTs). 15 TNTs are thin protrusions formed of actin microfilaments that transfer cytoplasm and organelles between connected cells.…”

MRI tracking reveals selective accumulation of stem cell-derived magneto-extracellular vesicles in sites of injury

“…1C. In brief, the synthesized SPIO-His nanoparticles were first loaded into purified EVs by electroporation as described previously (25). The resulting solution containing a mixture of free SPIO-His and magneto-EVs was purified using a Ni-NTA column.…”

“…produce EVs markedly higher than other types of stem cells (25). Considering that stem cell derived EVs lack nuclei, iPSC-derived EVs are attractive without the concerns of genetic instability and tumorigenicity associated with the administration of whole iPSCs (26,27).…”