Stem Cell-derived Extracellular Vesicles Combat the Aging Process

Review of “Highly purified human extracellular vesicles produced by stem cells alleviate aging cellular phenotypes of senescent human cells” from STEM CELLS by Stuart P. Atkinson

Recent research has described how extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) may represent a safe and efficient approach to the treatment of a range of conditions including cardiovascular diseases, radiation damage to bone marrow hematopoietic cells, fracture healing, and neurodegeneration (See a great review from STEM CELLS here) [1]. Unfortunately, the limited proliferation of human patient-derived MSCs and the inefficient production and purification of clinical‐grade EVs represent significant hurdles.

As an alternative source, researchers from the laboratories of  Linzhao Cheng and Vasiliki Mahairaki (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) assessed EVs derived from human induced pluripotent stem cells (iPSCs) given the general lack of studies [2-4] (See the related STEM CELLS article here!). Writing in STEM CELLS, Liu et al. employed international standards for EV characterization and purification [5, 6] to establish that both iPSC‐EV and MSC‐EV treatments promoted cell proliferation and alleviated senescence, thereby highlighting EVs, and especially iPSC-EVs, as an exciting means to combat the aging process and treat degenerative diseases [7].

The authors first expanded both iPSCs and MSCs in a chemically defined culture medium that lacked EVs and discovered that while the two populations of highly purified EVs exhibited the same size, iPSCs generated 16-fold more EVs than MSCs derived from the bone marrow, umbilical cord, and iPSCs. Interestingly, the treatment of MSCs and endothelial cells with EVs established that iPSC-EVs entered cells more efficiently than MSC-EVs, thereby highlighting the optimal nature of iPSC-EVs when compared to MSC-EVs. 

While treatment with either population of EVs failed to affect the proliferation of early passage cells, the treatment of MSCs undergoing replicative senescence or an MSC-based model of premature aging associated with senescence [8] with highly purified EVs promoted an increase in cell proliferation and a reduction in various signs of cell senescence, with iPSC-EVs providing a marginally better effect that MSC-EVs. Mechanistically, the teams discovered that EVs from both stem cell types contained elevated levels of peroxiredoxin intracellular antioxidant proteins that effectively reduced levels of reactive oxygen species, thereby reducing oxidative stress and associated cellular aging.

The authors of this interesting new study now hope to independently validate their EV purification scheme and further improve EV purification via the application of methods such as anion exchange chromatography and explore additional bioactive molecules involved in the alleviation of senescence within EVs. Furthermore, they hope to test the in vivo amelioration of aging‐associated phenotypes in small animal models in the hope of generating a safe and efficient means to combat the aging process and treat degenerative diseases.

For more on stem cell-derived EVs and the battle against aging-related disorders, stay tuned to the Stem Cells Portal!

References

1. Phinney DG and Pittenger MF, Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. STEM CELLS 2017;35:851-858.
2. Bobis-Wozowicz S, Kmiotek K, Sekula M, et al., Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior. STEM CELLS 2015;33:2748-2761.
3. Ding Q, Sun R, Wang P, et al., Protective effects of human induced pluripotent stem cell‑derived exosomes on high glucose‑induced injury in human endothelial cells. Experimental and Therapeutic Medicine 2018;15:4791-4797.
4. Saito S, Hiemori K, Kiyoi K, et al., Glycome analysis of extracellular vesicles derived from human induced pluripotent stem cells using lectin microarray. Scientific Reports 2018;8:3997.
5. Lötvall J, Hill AF, Hochberg F, et al., Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. Journal of Extracellular Vesicles 2014;3:26913.
6. Witwer KW, Soekmadji C, Hill AF, et al., Updating the MISEV minimal requirements for extracellular vesicle studies: building bridges to reproducibility. Journal of Extracellular Vesicles 2017;6:1396823.
7. Liu S, Mahairaki V, Bai H, et al., Highly Purified Human Extracellular Vesicles Produced by Stem Cells Alleviate Aging Cellular Phenotypes of Senescent Human Cells. STEM CELLS 2019;37:779-790.
8. Kubben N, Zhang W, Wang L, et al., Repression of the Antioxidant NRF2 Pathway in Premature Aging. Cell 2016;165:1361-1374.