Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species

Khánh, Vương Cát; Yamashita, Toshiharu; Ohneda, Kinuko; Tokunaga, Chiho; Kato, Harumi; Osaka, Motoo; Hiramatsu, Yuji; Onodera, Osamu

doi:10.1038/s41598-020-74444-8

Cited by 33 publications

(21 citation statements)

References 51 publications

(68 reference statements)

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“…A recently described method for rejuvenation of human MSCs employs extra cellular vesicles collected from infant MSCs which are used to treat MSCs from elderly persons. In response to this treatment downregulation of ROS production in the elderly cells was observed and furthermore a better functionality regarding their ability in decreasing necrotic areas in diabetic mouse models was observed ( Khanh et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity

Wruck

Graffmann

Spitzhorn

et al. 2021

Front. Cell Dev. Biol.

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Despite the uniform selection criteria for the isolation of human mesenchymal stem cells (MSCs), considerable heterogeneity exists which reflects the distinct tissue origins and differences between individuals with respect to their genetic background and age. This heterogeneity is manifested by the variabilities seen in the transcriptomes, proteomes, secretomes, and epigenomes of tissue-specific MSCs. Here, we review literature on different aspects of MSC heterogeneity including the role of epigenetics and the impact of MSC heterogeneity on therapies. We then combine this with a meta-analysis of transcriptome data from distinct MSC subpopulations derived from bone marrow, adipose tissue, cruciate, tonsil, kidney, umbilical cord, fetus, and induced pluripotent stem cells derived MSCs (iMSCs). Beyond that, we investigate transcriptome differences between tissue-specific MSCs and pluripotent stem cells. Our meta-analysis of numerous MSC-related data sets revealed markers and associated biological processes characterizing the heterogeneity and the common features of MSCs from various tissues. We found that this heterogeneity is mainly related to the origin of the MSCs and infer that microenvironment and epigenetics are key drivers. The epigenomes of MSCs alter with age and this has a profound impact on their differentiation capabilities. Epigenetic modifications of MSCs are propagated during cell divisions and manifest in differentiated cells, thus contributing to diseased or healthy phenotypes of the respective tissue. An approach used to reduce heterogeneity caused by age- and tissue-related epigenetic and microenvironmental patterns is the iMSC concept: iMSCs are MSCs generated from induced pluripotent stem cells (iPSCs). During iMSC generation epigenetic and chromatin remodeling result in a gene expression pattern associated with rejuvenation thus allowing to overcome age-related shortcomings (e.g., limited differentiation and proliferation capacity). The importance of the iMSC concept is underlined by multiple clinical trials. In conclusion, we propose the use of rejuvenated iMSCs to bypass tissue- and age-related heterogeneity which are associated with native MSCs.

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Section: Resultsmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity

Wruck

Graffmann

Spitzhorn

et al. 2021

Front. Cell Dev. Biol.

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“…No experimental evidence for the inclusion of SOD3 into exosomes exist, but recent findings show that mesenchymal stem cells release extracellular vesicles encompassing SOD3, and importantly that these vesicles have the capacity to modulate the redox conditions of recipient cells [ 110 , 111 ]. Although no direct corporation between NOX2 and SOD3 has been reported, it is intriguing to speculate that exosomes may encompass both enzymes to produce hydrogen peroxide at the target cell.…”

Section: Sod3 and Nox2 Interactions At The Macrophage Cell Surfacementioning

confidence: 99%

Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

Petersen

Poulsen²,

Matthiesen

et al. 2021

Antioxidants

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Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells.

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“…NANOG also restores COL3 expression and thus stabilizes extracellular matrix synthesis [247]. The use of ESC-Exos has also been shown to rejuvenate endothelial cells, enhance angiogenesis, reduce ROS levels, and promote pressure ulcer regeneration in aging mice [248,249]. The use of exosomes, in contrast to reprogrammed cells, is not accompanied by any oncological risks and therefore seems to be a very promising and interesting direction in antiaging.…”

Section: Epigenetic Approaches To Stem Cell Rejuvenationmentioning

confidence: 99%

Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation

Samoilova¹,

Белопасов

Ekusheva³

et al. 2021

JPM

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This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.

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Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species

Cited by 33 publications

References 51 publications

Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity

Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity

Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation

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