Very Small Embryonic-Like Stem Cells: Are They Real?

Testing hypotheses is usually considered the driving force that advances science; however, there is another force that not only advances science, it can also make science fun and engaging to watch: that driving force is controversy. The history of science is riddled with controversies. Perhaps, the most immediate that comes to mind is the controversial future use of induced pluripotent stem cells [1]. However, in the late 1980s and early ‘90s, one of the more overwhelmingly heated controversies dealt with how cells moved, by membrane flow or actin-based, focal adhesion. It was so heated, I remember sitting in the audience at a regional cell biology meeting, where insults were flung between rival laboratories during question and answer periods. Interestingly, as of 2013, what has emerged from that area of research is a general overarching theme that neither set of ideas was wrong. In fact, there are many ways of accounting for cell shapes and steady motion [2]. That was then, this is now.In this volume of SCD, fuel for a new generation of controversy resides in the evolution of very small embryonic-like stem cells (VSELs) [3]. Overall, the data the authors put forth for the existence of these cells are compelling. In fact, it is difficult to shake the feeling that the authors are on to something here. In Anand et al., the work revolves around efforts for restoring spermatogenesis to male cancer patients. The most striking data they show is the ability of distinct bone marrow cells to regenerate spermatogenesis within testes depleted of spermatogonia as a result of chemical ablation. However, before those data are presented, the hypothesis that VSELs are at the core of this regeneration is tested. Anand et al. clearly show that routine busulfan treatment virtually obliterates the proliferating spermatogonial cell population, but left behind within seminiferous tubules is a small subset of cells that express Sca-1 and Oct4A (the nuclear form). They then use cell sorting flow cytometry to characterize these cells by size and marker identification, first in mice and then in humans who are azoospermic survivors of childhood cancers. These latter sets of data are what really begin to raise eyebrows. The fact that a clinical similarity between the mouse model and a relatively equivalent set of human patients adds fuel to the controversy that VSELs may actually exist, furthering the need for more detailed analyses. It is the mesenchymal cell transplant data that really take us beyond raising eyebrows and more toward opening eyes. Histological sections of busulfan-treated testes that were transplanted with bone marrow cells two months earlier show striking examples of sperm production. The sperm appear to be morphologically normal and motile. How does the VSEL story fit in with the transplant data? The answer put forth is that the somatic cell transplants reengage spermatogenesis by replenishing the seminiferous tubule and somatic (ie, Leydig cells) compartment niches with a source of growth factors and cytokines. So where is the controversy? It comes from Irv Weismann’s laboratory, which has cast doubt on the existence of VSELs. An article from NBC News health (www.nbcnews. com/health/bioethicist-failed-search-controversial-formstem-cells-shows-danger-mixing-6C10776643) illustrated Dr. Weismann’s point of view. In essence, using a good bank of experiments, Weismann’s group could not confirm the existence of VSELs [4]. Specifically, they determined that most events within the VSEL flow cytometry gate had little DNA and the cells corresponding to these events could not form spheres. They also determined that these cells did not express Oct4 and could not differentiate into blood cells. The NBC News health story also delved into ethical issues between the adult stem cell and embryonic stem cell circles with respect to the potential of VSELs; however, the topic could turn this short editorial into a dissertation. So, I shall save that discussion for another day. The controversy, though, remains impassioned (as of July 24th 2013) as the blog article from SCOPE supported by Stanford University Medicine, http://scopeblog.stanford.edu/ 2013/07/24/very-small-embryonic-like-stem-cells-may-notexist-say-stanford-researchers/, enables members from both laboratories to rebut each other’s points about the existence or not of VSELs. So far the debate remains meaningful and civil with both parties making sound points. Also, Anand et al. in this volume of SCD make further comments on the NBC News health article and the work by Miyanishi et al. (2013) [4]. From an outsider’s point of view, these types of polarized points can keep science and the scientific community enthralled in a ‘‘which way is the science going to take us’’ storyline. Is one set of ideas going to triumph about the existence of VSELs or will there eventually be a resolution where both sides’ hypotheses contain aspects that are