Update on VSEL controversy

by Alexey Bersenev on January 11, 2014 · 0 comments

in other adult stem cells

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We continue to follow “VSEL controversy” and keep you updated. Since the last “Ratajczak’s response to criticism“, a few new papers came up. First and the most important paper is “The proper criteria for identification and sorting of VSEL“. Ratajczak kept his promise and published detailed protocol and proper criteria. This is a good thing. But I’d like to remind you guys, that his group already published a number of “detailed/ clarifying and optimized VSEL protocols” in the past (ex: 1, 2, 3). Now we have one more, and probably, not the last one. The second thing, I’d like to note – I think, it’s a big mistake to publish anything clarifying on a peak of controversy under “paywall”. It is the best interest of authors, to disseminate their work as much as possible (= free access) and discuss it with peers as soon as possible. Stem Cell and Development journal is not very exotic, but for example, my institution has no access to it.

Now, I’d like to say, that Ratajczak did much better job in the current review to clarify some issues, compare to previous paper. He left emotions and inflammatory language (“competitors vicious attack”) behind and provided analysis of possible issues, which caused the lack of reproducibility:

The major concern with the work of some groups that reported negative data [31-33] is that, despite their claims, they did not follow our published protocol for isolating VSELs. However, we have to admit that these are not trivial sorting strategies, and failure to isolate these rare cells occasionally happens even in our experienced in VSELs sorting hands. Nevertheless, most of these difficulties could have been eliminated or greatly minimized if these groups [31-33] had first contacted us.

Among other things, he admits, that “more work should be done to characterize human VSELs” and “VSELs are, to some degree, heterogenous” and “we still can not expand them ex vivo“. The authors did a simulation of Dulak’s group gating strategy and, also addressed the discrepancies from Weissman’s and Alt’s studies. Basically, they pointed out, that “real VSEL population was excluded” from sorting, because of wrong gating strategy or/ and wrong staining. For example, Annexin V staining:

… the entire fraction of CD45–/Lin–/Sca-1+/c-kit–/KDR– cells was excluded by these authors from further sorting [32], because it was deemed “apoptotic”, while it most likely contained not only real Annexin V+ FSClow SSCdim/hi apoptotic objects, but in addition, VSELs. Importantly, we have reported [48] that healthy normal cells (including VSELs and HSCs) may bind Annexin V following lysis of RBCs due to microvesicle/microparticle release and posphatydylserine transfer to the membranes of the normal cells.

The next interesting thing is discussion about “pluripotency of VSELs“. These cells pass all in vitro pluripotency tests (3 germ layers differentiation), but fail in vivo tests (teratoma formation). Ratajczak is not using term “pluripotent” any more, because of disagreement on this, but he calls to use “embyonic-like” in nomenclature.

The next paper is by Russell Taichman group (with some NeoStem’s people in it) – VSEL cells represent multipotent tissue progenitors. Taichman’s group attempted to test self-renewal of VSELs in serial transplant experiment and they failed. Maybe that’s why they decide to use “progenitor” term instead of “stem”. They showed differentiation in multiple lineages of human and mouse VSELs in vitro by expression of markers. They also showed differentiation of VSELs in ossicles with marrow in bone defects and subcutaneously. VSELs expressed markers of multiple lineages from 2 germ layers (not all 3). No teratomas or any other tumors were observed. Based on these data, the authors continue to juggle with nomenclature and called VSELs “multipotent”, avoiding of “pluripotent” term.

I have multiple questions about this study, but couple, related to NeoStem’s trials are the following:

  • Should be VSELs induced in vitro before transplantation?
  • What is benefit of VSELs expressing markers of multiple lineages in site of bone defect and subcutaneously? I’d stay away from cells expressing everything and migrating outside of site of injury.
  • What is advantage of VSELs compare to conventional MSCs, widely used for skeletal tissues repair?

Taichman wrote about the controversy:

Recently several groups have reported that they have been unable to isolate VSEL cells and suggest there
is insufficient animal data to warrant human clinical trials [28-30]. There is no doubt that isolation of VSEL cells and their cultivation is a difficult endeavor.
… we believe that the reasons for the differences in experimental results are of a technical nature.
… Nevertheless some of the critiques of the VSEL cell field are valid; more systematic studies are needed.

By admitting that “more studies should be done with human VSELs” and “some of the critiques of the VSEL cell field are valid”, Ratajczak and Taichman are trying to say – VSELs are not ready for trials yet. Aren’t they?

I’m not very happy about the fact that discussion largely moved to “rigid and paywalled” Stem Cells and Development journal. It is very slow with lack of readability. Not good for the field. I’d like to bring one more commentary from this journal’s editorial by Ian Gallicano:

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 correct? I actually don’t think we know yet…

Finally, I’d like to notice one more recent paper: VSELs are not discarded by standard cord blood bank processing (as opposite to previous study).

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