VSELs – State of the Art Regen Med or Fairy Dust?
There has been a two-decade-long debate in Regenerative Medicine concerning tiny stem cells. I had largely forgotten about these Very Small Embryonic Like (VSEL) stem cells until a patient came into the clinic claiming that he had been treated with them. So what is this and why should we care? Let’s dig in.
What Are VSELs?
The idea behind Very Small Embryonic Like (VSEL) stem cells is that they are small and like embryonic stem cells, they can differentiate into many different cell types. They are supposed to be produced largely in the bone marrow but can mobilize from there into the blood under certain circumstances.
VSELs were discovered by a professor at the University of Louisville and in humans, they are about the size of a red blood cell (7 nm) (1). I was first introduced to the concept of these cells way back in about 2008 because the company I was consulting for (Neostem) had a contract to work on VSEL research with the lead researcher in this area, Dr. Ratajczak.
It is thought that VSELs originate from the early cells in an embryo and are deposited in developing organs as the embryo grows. It’s also thought that they play a role as a backup population for tissue-committed stem cells. There are stem cells that live in all of your organs that help repair things. So the idea would be that if the local stem cells were depleted or couldn’t function, VSELs would step in.
VSELs are not usually active (called quiescent) but are activated during stress situations and mobilized into the circulation. The number of these cells decreases with age and they give rise to mesenchymal stem cells. They are also very controversial cells.
The Empire Strikes Back
If Dr. Ratajczak at the University of Louisville was the rebel alliance, then Irv Weissman at Stanford would be the Empire. Irv is one of the best-known stem cell scientists in the world and has many firsts in regen med like figuring out how hematopoietic stem cells work (blood-forming stem cells or HSCs). Irv is very much the stem cell establishment and Ratajczak is very much the upstart wanting to reorganize the way the establishment sees how stem cells work.
In 2013, Dr. Weissman published a paper that blew up the VSEL research world (3). Basically, Irv tried to find VSELs in mouse bone marrow and didn’t find any. This was a little like the death star blowing up the planet Alderon. What was an active and growing research interest in VSELs came to a screeching halt.
Did Irv Do the Research Correctly?
We like to think of scientists like monks working in the ivory tower without any consideration to things like fame or money. While that may be true for those in pure science, many applied science professors in the stem cell field have significant financial conflicts of interest. So did Irv have a conflict of interest reason to get rid of VSELs? Ratajczak later wrote:
“However, while we were working on better characterizing these cells and exploring possible applications in animal models in vivo, the very existence of VSELs was questioned. It is regrettable that, having a problem with VSEL purification, which requires a special gating protocol, this group did not follow the detailed protocol for VSEL isolation previously published in Current Cytometry Protocols (https://currentprotocols.onlinelibrary.wiley.com/doi/abs/10.1002/0471142956.cy0929s51). This paper 7 slowed progress in this area.”
What Is the Actual Research on the Clinical Use of VSELs?
We really don’t know whether VSELs are real. Looking at all of the data, I could maybe convince myself that they exist. However, do we have any clinical data that VSELs can treat any human condition? Nope. There are no clinical trials or even case series listed in the US National Library of Medicine.
So what do we know about VSELs and disease? The advocates for VSELs have published papers showing that they’re mobilized into the bloodstream during heart attacks, strokes, and chronic respiratory disease (4,5,7). We know that when mice are exposed to intermittent low oxygen (hypoxia) that VSELs mobilize into the bloodstream (6). What we don’t know is that if you isolate these cells and use them to treat someone that it does any good.
Trigeminal Neuralgia Treated with VSELs?
A young patient came to my office with Trigeminal Neuralgia (TN) who stated that he had gotten VSEL treatment. He described blood being taken from which VSELs were isolated and then activated using some sort of light and temperature. I looked all of this up on the clinic website and this description seems accurate. The patient was told that the VSELs would cross his BBB and fix his trigeminal nerve.
The first issue is that VSELs live in the bone marrow and are only mobilized in times of severe illness or stress. Hence, that first part of the story doesn’t make great sense. VSELs don’t generally live in the bloodstream of healthy patients in large numbers.
Next, isolating VSELs from other blood cells would involve binding a fluorescent antibody to the cells and then using cell sorting (FACS) or some other commercial system like a magnetic separation column (8). The former is a complex lab research machine and the latter is a purpose-built kit device used in labs. Neither of these would be legal to use in a clinical patient.
Both of these machines would require high-level research staff with experience separating cells via surface markers, not medical assistants in a clinic. For example, a FACS machine (we have one in our lab) costs about 250K and as you see above, according to Ratajczak, even the experts in Dr. Weissman’s lab at Stanford couldn’t figure out how to use it properly to isolate VSELs. So if PhDs couldn’t do it, what’s the chance that a medical assistant can? Finally, there is no commercially available magnetic separation column meant for research that you could buy and use illegally on a patient.
However, for argument’s sake, let’s say that you could isolate VSELs (a big if). Now the problem is that we have no published research on the activation of VSELs using light or temperature.
How would VESLS help trigeminal neuralgia? The problem is that while delivering them intravenously would be easy, how would these cells get across the Blood-Brain Barrier (BBB)? This is the thing that prevents the bad guys like bacteria from getting into the brain. How small does a cell have to be to get across the BBB (9)? Very, very small or 1 nm or less. How big are VSELs? Way too big at 7 nm.
So even if you could isolate VSELs in a clinic (it would actually take an advanced research lab), activate them, and then infuse them intravenously, none would make it to the brain to help the fifth cranial nerve that causes TN. So this clinic’s story of using VSELs is a few sandwiches short of a picnic. That’s British slang that means not quite fully baked.
The upshot? There is conflicting data showing that VSELs are real. If they are real, there is no alternative medicine clinic capable of isolating them. In addition, there is no research that shows that you could activate them by using light or temperature. They are also way too big to cross the BBB and make their way into the brain. Finally, we have no published clinical data showing that they would do anyone any good. Hence, what sounds like a great story, doesn’t pass the regen med sniff test.
(1) Miyanishi M, Mori Y, Seita J, Chen JY, Karten S, Chan CK, Nakauchi H, Weissman IL. Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? Stem Cell Reports. 2013 Jul 24;1(2):198-208. doi: 10.1016/j.stemcr.2013.07.001. PMID: 24052953; PMCID: PMC3757755.
(2) Bhartiya D, Shaikh A, Anand S, Patel H, Kapoor S, Sriraman K, Parte S, Unni S. Endogenous, very small embryonic-like stem cells: critical review, therapeutic potential and a look ahead. Hum Reprod Update. 2016 Dec;23(1):41-76. doi: 10.1093/humupd/dmw030. Epub 2016 Sep 10. PMID: 27614362.
(3) Miyanishi M, Mori Y, Seita J, Chen JY, Karten S, Chan CK, Nakauchi H, Weissman IL. Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? Stem Cell Reports. 2013 Jul 24;1(2):198-208. doi: 10.1016/j.stemcr.2013.07.001. PMID: 24052953; PMCID: PMC3757755.
(4) Wojakowski W, Ratajczak MZ, Tendera M. Mobilization of very small embryonic-like stem cells in acute coronary syndromes and stroke. Herz. 2010 Oct;35(7):467-72. doi: 10.1007/s00059-010-3389-0. PMID: 20981396.
(5) Guerin CL, Blandinières A, Planquette B, Silvestre JS, Israel-Biet D, Sanchez O, Smadja DM. Very Small Embryonic-like Stem Cells Are Mobilized in Human Peripheral Blood during Hypoxemic COPD Exacerbations and Pulmonary Hypertension. Stem Cell Rev Rep. 2017 Aug;13(4):561-566. doi: 10.1007/s12015-017-9732-6. PMID: 28285391.
(6) Gharib SA, Dayyat EA, Khalyfa A, Kim J, Clair HB, Kucia M, Gozal D. Intermittent hypoxia mobilizes bone marrow-derived very small embryonic-like stem cells and activates developmental transcriptional programs in mice. Sleep. 2010 Nov;33(11):1439-46. doi: 10.1093/sleep/33.11.1439. PMID: 21102985; PMCID: PMC2954693.
(7) Skirecki T, Mikaszewska-Sokolewicz M, Godlewska M, Dołęgowska B, Czubak J, Hoser G, Kawiak J, Zielińska-Borkowska U. Mobilization of Stem and Progenitor Cells in Septic Shock Patients. Sci Rep. 2019 Mar 1;9(1):3289. doi: 10.1038/s41598-019-39772-4. PMID: 30824730; PMCID: PMC6397313.
(8) Monti M, Imberti B, Bianchi N, Pezzotta A, Morigi M, Del Fante C, Redi CA, Perotti C. A Novel Method for Isolation of Pluripotent Stem Cells from Human Umbilical Cord Blood. Stem Cells Dev. 2017 Sep 1;26(17):1258-1269. doi: 10.1089/scd.2017.0012. Epub 2017 Jun 4. PMID: 28583028.
(9) Medscape. Nanobiotechnology-Based Strategies for Crossing the Blood–Brain Barrier. Nanomedicine. 2012;7(8):1225-1233. https://www.medscape.com/viewarticle/770396