Hey @Olafurpall this is a good point… but, I honestly think there is a massive amount of publication bias, and probably a good amount of fabrication, falsification or methodological problems in this research area. And I say this as somebody (hopefully) credible in the field, have spoken at ISEV before, invited to give talks on this topic etc.
Of course it’s about more than just raw numbers. You’re right that most EVs in the blood aren’t from MSCs (they’re from blood cells, endothelial cells, and smaller amounts originating from organs). However, I am just use that as an example to illustrate why I find the whole “idea” to be lacking credibility.
I will say that I find a lot of the animal studies hard to believe, and in my lab we’ve actually tried replicating a few key findings from some big studies, and we’re almost never able to. Let me give you a concrete example (Just note, this relates to plasma EVs, not MSC derived EVs, and should be more generalisable). There’s a Nature Aging paper here: Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism - PubMed which claims taking EVs from the blood of young mice and injecting them into old mice basically fixes almost every pathology of aging. They show better sperm counts, heart function, physical performance etc etc. They trace it down to a few EV miRNAs, targeting mitochondrial PGC-1a.
Well, a couple years ago got some old mice, (~90 weeks old), and some young mice (8-12 weeks old), and we took blood samples, isolated EVs from the plasma, and we tested them in a bunch of in vitro models. We found almost no statistically significant differences at all across the board, so we actually gave up on the project. (See how the publication bias comes into play). When I saw this paper, we dug out our cell cDNA samples and looked at PGC-1a expression (the hallmark discovery of this paper) - no change in 3 different cell lines. We also tried measuring the miRNAs miR-29a, miR-34a etc in the EVs from young and old, and didn’t find any differences. In fact, I seem to recall that at least one of them wasn’t even present/detectable, using multiple primers.
So maybe what they report in the paper is true, but perhaps it only works in their lab, in their mice, in their hands. So is the finding/hype applicable to anything outside of that? Who knows.
You can also find other papers, like this one in Aging Cell (
2020 - Alibhai et al. - Cellular senescence contributes to age-dependent changes in circulating extracellular vesicle cargo and function.pdf (1.6 MB) that reports different findings, different upregulated miRNAs etc. If you look at what they say is higher and lower in the cargo, it has no resemblance to the other study.
So you’re right about exosomes being far from a uniform entity, and that’s part of why I find it so hard to get excited about any of this stuff. There’s also the apparently massive gaps in our knowledge. For example, all the hype about miRNAs, but apparently they are extremely rare: https://www.pnas.org/doi/10.1073/pnas.1408301111
With small molecules like Rapamycin the findings are mostly reproducible because we can at least standardise the compound and the dose. So personally, until somebody can explain what the active substance is, what the dose is, and roughly how this works, I remain extremely sceptical of exosomes.
