More on Very Small Embryonic-Like Stem Cells

By way of a follow-up to an interview last month on what are termed very small embryonic-like stem cells (VSELs), here is a recent open access review paper that outlines the present state of knowledge on this topic - which has some relevance to studies of longevity in addition to the broader field of regenerative medicine:

Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation - an update and comparison to other primitive small stem cells isolated from adult tissues:

One of the most intriguing questions in stem cell biology is whether pluripotent stem cells (PSCs) exist in adult tissues. Several groups of investigators employing i) various isolation protocols, ii) detection of surface markers, and iii) experimental in vitro and in vivo models, have reported the presence of cells that possess a pluripotent character in adult tissues. Such cells were assigned various operational abbreviations and names in the literature that added confusion to the field and raised the basic question of whether these are truly distinct or overlapping populations of the same primitive stem cells. Unfortunately, these cells were never characterized side-by-side to address this important issue. Nevertheless, taking into consideration their common features described in the literature, it is very likely that various investigators have described overlapping populations of developmentally early stem cells that are closely related.


[We believe that] during embryogenesis, some PSCs give rise to [populations of less potent tissue-committed stem cells (TCSC)s] but some survive in adult tissues as a backup population of PSCs that renews the pool of TCSCs over time. In this scenario, PSCs are precursors of TCSCs during organ/tissue rejuvenation and a source of these cells in emergency situations when organs are damaged (e.g., heart infarct or stroke).


a main goal of the molecular analysis studies was to explain why VSELs do not fulfill the in vivo gold-standard criteria expected for PSCs (complementation of blastocyst development and teratoma formation in immunodeficient animals), which are seen with [embryonic stem cells] and [induced pluripotent stem cells]. To explain this discrepancy, we observed that VSELs, in a similar manner as late migratory primordial germ cells (PGCs), modify the methylation of imprinted genes, preventing them from uncontrolled proliferation and explaining their quiescent state in adult tissues


we proposed a hypothesis that relates aging, longevity, and insulin/insulin-like growth factors signaling (IIS) to the abundance and function of pluripotent VSELs deposited in adult murine tissues. We postulate that a decrease in the number of these cells due to prolonged IIS negatively affects the pools of TCSCs in various organs and has an impact on tissue rejuvenation and life span. In support of this notion, we observed a significantly higher number of VSELs in long-living murine strains (e.g., Laron dwarfs and Ames dwarfs), whose longevity is explained by low levels of circulating IGF1 and a decrease in IIS. By contrast, the number of VSELs is reduced in mice with high levels of circulating IGF1 and enhanced IIS (e.g., growth hormone-overexpressing transgenic mice) compared to normally aging littermates.


a chronic increase in caloric uptake that elevates circulating levels of IGF1 and [insulin] may contribute over time to depletion of [VSELs] from adult tissues, affect the generation of VSEL-derived TCSCs, and thus negatively affect life span. This explains why mice that have high levels of circulating blood plasma IGF1 and enhanced IIS display accelerated depletion of VSELs and have a shorter lifespan than age-matched littermates.

Interestingly, it is often the case that life science researchers spend years investigating the same entity within the body from different directions, working in comparative isolation from one another and developing quite divergent nomenclature. It is only later on that lines are drawn between the dots and some unity imposed on that area of research - this is more or less what happened for lipofuscin, for example, the build up of many mixed harmful chemicals inside cells that occurs with aging. Lipofuscin contributes to many different age-related conditions, and for years went by many different names in different subfields of medical and biological science, and few of the researchers were picking up on parallel and useful research outside their specialty.

So, even aside from the evidence amassed, it is entirely plausible that there is a great deal of this unification and synthesis yet to happen for portions of stem cell research - but on the other hand cells are very complicated beasts. To a certain degree calling something a stem cell or a particular type of stem cell at this time is a form of pidgeonholing in the face of complexity: a cell is quite capable of being sort of a stem cell or somewhat stem cell-like, and different types of stem cell might be as different from each other as they are from non-stem cells - and their categories all blur at the edges. Stemness isn't the result of a single switch, and is rather much more like a collection of linked controlling mechanisms.

Insofar as this all touches upon calorie restriction (CR) and its effects on health and longevity, we should absolutely expect that calorie restriction in some way affects stem cell populations for the better. Stem cells are an integral mechanism of health, and it would be hard to explain how CR improves near every measure of health, slows aging, and extends life in diverse animal species without it causing some improvement in stem cell capacity and operation in addition to its other lower level mechanical effects.


This result seems to support the "programmed aging" theory
- unless IGF-1 signalling somehow causes "wear and tear".

It seems more likely that it ratchets cell populations forward in the "stem ---> senescent" phenotype spectrum.

Posted by: Lou Pagnucco at April 12th, 2012 7:12 PM

Recently i have isolated VSEL stem cells in mice bone marrow with FACS and the percentage of these cell was 1% in a day i'm working on these cells and differentiate them.

Posted by: morteza at June 30th, 2012 2:29 AM
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