It is widely accepted that stem cells are involved in tissue regeneration. It is also widely accepted that (in most organs) stem cells are vanishingly rare. So: if there doesn’t happen to be a stem cell adjacent to a site of damage, how can stem cells be involved in the process of tissue repair?

One possible answers: There might be more stem cells than we think, because we’ve been missing them for some reason. This possibility is strongly supported by the recent findings of Zuba-Surma et al., who have discovered a population of tiny pluripotent cells (termed, appropriately, very small embryonic-like, or VSELs) scattered throughout the body.

Very small embryonic-like stem cells in adult tissues—Potential implications for aging
Recently our group identified in murine bone marrow (BM) and human cord blood (CB), a rare population of very small embryonic-like (VSEL) stem cells. We hypothesize that these cells are deposited during embryonic development in BM as a mobile pool of circulating pluripotent stem cells (PSC) that play a pivotal role in postnatal tissue turnover both of non-hematopoietic and hematopoietic tissues. During in vitro co-cultures with murine myoblastic C2C12 cells, VSELs form spheres that contain primitive stem cells. Cells isolated from these spheres may give rise to cells from all three germ layers when plated in tissue specific media. The number of murine VSELs and their ability to form spheres decreases with the age and is reduced in short-living murine strains. Thus, developmental deposition of VSELs in adult tissues may potentially play an underappreciated role in regulating the rejuvenation of senescent organs. We envision that the regenerative potential of these cells could be harnessed to decelerate aging processes.

Note that both VSEL number and potency diminish with age, consistent with the decrease in proliferative and regenerative capacity that we see in older animals. (And recall that diminishing stem cell potency is just one side of the story: over the course of aging, tissue microenvironments themselves grow more hostile to stem cell growth and function).

The small size of the VSELs, along with their dispersal throughout the body, might explain why they’d been missed up until now. It makes sense that cells devoted to long-term storage of regenerative potential would be very little: other than surviving and maintaining the ability to respond to proliferative signals, they wouldn’t really have much in the way of functional requirements, and wouldn’t need much more than a nucleus, a membrane, and extremely vigilant signal-transduction pathways — the latter ready to awaken the dormant cell when it’s time to turn into a proper stem cell, divide, and differentiate. In a sense, then, these VSELs are not so much progenitors as “progenitor progenitors”, the of regenerative capacity lying silent until they are needed.

(Extending this admitted over-interpretation — small size, after all, does not mean low metabolism, but I’m reasoning by analogy to spores and other very small totipotent cellular forms — another advantage of keeping stem cells metabolically inactive is that they would be less likely to suffer mutations or other damage that could convert them into cancer stem cells.)

Required skepticism: VSELs are both brand new and (so far as I can tell) idiosyncratic to a single group’s work. Before we get too worked up about this, I’d like to see the work reproduced by other labs and in other systems. Hopefully that sort of confirmation is already underway.