The stem cell universe is populated by sometimes mysterious acronyms (see an image of a whole alphabet stem cell acronym soup), many of which refer to specific kinds of stem cells including one nebulous type called MUSE cells.
MUSE cells clinical trials
I’m not convinced that MUSE cells exist, but oddly there appear to be four clinical trials ongoing in Japan based on MUSE cells.
So somebody believes in them.
Is the clinical work using MUSE cells in Japan allowed because of the more permissive regenerative medicine regulatory framework there?
I found just over 50 papers with MUSE in the title on Pubmed. I found no registered trials on them on Clinicaltrials.gov.
Other dubious “stem cells”
MUSE stands for MUltilineage differentiating Stress Enduring cells. Right off the bat MUSE’s full name reminds me of the debunked STAP cells. The STAP acronym stands for Stimulus-Triggered Acquisition of Pluripotency. STAP cells were supposed pluripotent stem cells made by stressing non-stem cells out, most famously by dipping them in an acid bath. That was bogus.
MUSE are also supposed to be pluripotent stem cells, this time coming from adult tissues and apparently can deal with stress pretty well based on their name. Extreme stress is reported as a way to enrich for MUSE cells as it kills other cell types.
When I think of MUSE, another supposed stem cell type called very small embryonic stem cell-like (VSEL) cells comes to mind too. They are yet another member of the group of supposed adult pluripotent stem cell class. I don’t believe VSEL naturally exist and tend to think of them as the Sasquatch of the stem cell field.
It’s concerning that in each case only a few scientists apparently can find any of these mysterious cell types. So who does believe in MUSE? A few groups, but their main proponent is Professor Mari Dezawa.
She and her team recently had a massive paid ad (that looked like a regular Nature article) in Nature on MUSE that I called out for being a concerning hybrid ad-article that many readers might confuse as peer-reviewed science in Nature. After I raised my concerns, Nature pulled the MUSE ad-article. That situation didn’t exactly boost my confidence in MUSE.
Why are MUSE so hard to find?
Dezawa has gone so far as to assert in a paper that MUSE present in non-stem cell cultures such as of fibroblasts might explain the production of iPS cells rather than actual full reprogramming occurring, which is a controversial idea.
So could MUSE cells actually exist despite broad skepticism?
I tend to doubt it, but how can we be 100% sure either way? It may be difficult.
To get some opinions, in recent months I reached out to a handful of scholarly stem cell scientists and none believed in MUSE cells.
Below is a quote from a past article I did on MUSE that also provides more background. I’m just including it here again rather than restating it anew (note that the experts I mentioned in this quote are mostly different than the ones I asked more recently):
“However, I am not so convinced that MUSE cells exist as a normal, easy to isolate population of stem cells that have substantial utility. Other experts with whom I talked feel likewise.
An NBC News article in 2013 on MUSE quoted Martin Pera, who expressed caution as well:
“Both the [Dezawa] work and the current study are interesting but preliminary,” Martin Pera, program leader of Stem Cells Australia, and a professor at the University of Melbourne, said. “Evidence that MUSE cells can actually turn into a wide range of mature functional body cells is somewhat limited.”
One puzzle admitted even by the researchers is that the MUSE cells do not form teratoma, a type of tumor generally readily produced in the laboratory by true pluripotent stem cells. Other purported adult pluripotent stem cells have also failed to make teratoma, raising skepticism, although if these cells were truly pluripotent their lack of teratoma forming activity would be good from a safety perspective.”
Isn’t it extra risky to do clinical trials with cells that seem so dubious? Certainly the trials are using some kind of cells, but what are they exactly? The trials are run by “Life Science Institute Inc., the group company of Mitsubishi Chemical.”
Do you believe in MUSE? Take our poll.
Very informative! Thank you everyone for your perspective.
What is the current thinking on these strange and wonderful cells…?
Tom
@Tom,
Most people I know are either highly skeptical of MUSE cells are outright think they don’t exist. A few folks think that they don’t exist naturally but can be forced into existence through stress treatment of cells kind of like was claimed for fake STAP cells. I think of MUSE and VSELS as similar in some ways as ideas. Very few people can consistently get these supposed cells, which is a red flag to me. There is concrete data suggesting VSELs cannot be isolated per Irv Weissman and I think that reflects somewhat on the MUSE cell claims too.
Hello,
by chance I stumbled in this blog. I am one of researchers that visited Dezawa’s lab and then reproduced in autonomous manner the experiments on Muse cells. Well, the data in our labs about basic biological properties of Muse cells are robust and reproducible. I mean growing after isolation, stress resistance, differentiation properties etc.
So in my opinion, it is not a question of belief. We are scientists I believe in what I do, I can repeat again and again and analyze.
My comment is: wait and see, if Muse cells are like all other “fake news” they will disappear from scientific horizon. Meanwhile I will strive to work on them and any collaboration is welcomed.
Regards
Thanks, Umberto. Do you think they are pluripotent or just multipotent?
Do they exist in vivo or are they created in part from the stress during the isolation process?
Dear Paul,
We are performing only in vitro experiments. According to our data, Muse cells can undergo spontaneous or induced differentiation in cell types with ecto-, exo-and endormal phenotypes .Obviously, in these conditions, as for other pluripotent stem cells, the in vitro differentiation does not produce full functional cells. The final proof of concept is the in vivo injection. For that I know the Dezawa’s group and others injected Muse cells in several disease models and obtained Muse differentiation. By the way this is completely different from what happens with mesenchymal stromal cells (MSCs) that work mainly by secreting growth factors and immunomodulators. This activity seems marginal in Muse cells.
About their existence in vivo. This is a very hot topic, at the moment I have no data to have a definitive answer. Indeed, I can tell you that you may isolate SSEA-3 positive cells from MSCs in a very reproducible way. They are around 1-3% of total population and these cells represent bona fide the Muse cells. If stress has a role then the isolation from different labs may greatly affect the percentage of Muse cells and this seems not to be the case. Anyway, many studies have to be carried out.
I am submitting a paper showing that proteome of Muse cells, iPSCs and MSCs are quite different and that Muse proteome is enriched in factors that may explain their stress resistance.
As you can see, the Muse situation seem different from previously identified pluripotent cells within MSCs. On the other hand I understand your note of caution.
Thank you for your attention and useful comments.
Regards
@Paul Knoepfler
https://ipscell.com/2019/11/dubious-muse-cells-are-in-4-japanese-stem-cell-trials/
I was initially reluctant to comment on a blog written 6 months ago. However, the more I thought about what you wrote, the more unfair the blog seemed. Let me comment on what appears to be your three principle objections to Muse cells.
• You objected to the name of Muse cells. Naming a newly discovered cell is the prerogative of scientists who discovered the cell. As you pointed out, the world of stem cell research is filled with acronyms, often inappropriate names of poorly defined cells. One example is mesenchymal stem cells (MSC), a misnomer because it is not clear that all MSC come from mesenchymal tissues or produce only cells of mesodermal lineages. Muse stands for “multilineage stress-enduring cells”. Muse cells produce cells of all three lineages (epi-, meso-, and endo- dermal) and tolerate stress. The name Muse seems appropriate to me.
• You questioned the clinical trials of Muse cells. You are not convinced that these cells exist and point out that the trials are not registered on http://clinicaltrials.gov. As you know, trial announcements on http://clinicaltrials.gov are neither required are nor verified. Mitsubishi (one of Japan’s largest industrial corporations) has committed hundreds of millions of dollars to do clinical trials of Muse cells in Japan, something they would not do without extensive vetting, testing, quality-controlled production of the cells, and of course regulatory approval. You said that you had conducted an informal poll of “a handful of scholarly stem cell scientists”. You then cited 7-year old comments by Martin Pera who said in 2013, “Both the [Dezawa] work and the current study are interesting but preliminary.” Pera also said, “… if these cells were truly pluripotent their lack of teratoma forming activity would be good from a safety perspective.” The work is no longer preliminary.
• You called Muse cells “dubious”. Muse cells apparently reminds you of “very small embryonic-like” (VSEL) cells and “Stimulus-Triggered Acquisition of Pluripotency” (STAP) cells. Some scientists (https://scopeblog.stanford.edu/2013/07/24/very-small-embryonic-like-stem-cells-may-not-exist-say-stanford-researchers/) could not confirm the existence of VSEL cells [1] and Haruko Obokawa reported STAP cells in a 2014 Nature article that she withdrew after accusations of falsified data (https://en.wikipedia.org/wiki/Stimulus-triggered_acquisition_of_pluripotency). Your suggestion that Muse cells are in the same category as VSEL and STAP cells is inappropriate. No claim of data fabrication has ever been leveled at Muse cells or Dezawa. Dezawa’s work [2-39] has been confirmed and extended by independent groups [40-68]. She and her colleagues published a book [28] at the end of 2018, describing her work with many collaborators, providing ample evidence that the cells are real and well-characterized, show safety and promise in preclinical studies, and are now being tested in rigorous clinical trials approved by the Japanese PMDA.
Wise Young MD PhD Rutgers University, Piscataway, NJ 08543-8082
References list: https://www.dropbox.com/s/h64l6cnpfn6u4fm/paul%20knoepfler%20response.docx?dl=0
For those who might be interested in more information concerning the “Muse” (CL2020) clinical trials that Mitsubishi is sponsoring, one trial is listed in http://clinicaltrials.gov
“The Clinical Trial of CL2020 Cells for Neonatal Hypoxic Ischemic Encephalopathy (SHIELD)” (https://clinicaltrials.gov/ct2/show/NCT04261335?term=CL2020&draw=2&rank=1). The Clinicaltrials.gov identifier is NCT04261335.
Five earlier clinical trials can be found at the NIPH Clinical Trial Search (https://rctportal.niph.go.jp/en/result). Search for “CL2020”.
A confirmatory study of CL2020 in patients with ST-elevation myocardial infarction ST-elevation myocardial infarction Life Science Institute Inc. 2019-12-10
A clinical study of CL2020 in patients with spinal cord injury spinal cord injury Life Science Institute Inc. 2019-07-03
A clinical study of CL2020 in patients with epidermolysis bullosa Epidermolysis bullosa Life Science Institute, Inc. 2018-12-20
A randomized, double-blind, placebo-controlled clinical study of CL2020 in ischemic stroke patient Ischemic stroke Life Science Institute, Inc 2018-09-06
Exploratory study of CL2020 in ST-elevation acute myocardial infarction ST-elevation myocardial infarction Life Science Institute. Inc. 2018-01-16
Thanks for your comment, Wise. I appreciate your view. I think we’ll just have to agree to disagree on MUSE cells.
Hi fellows
I dived into the Medline. MUSE cells are described in 66 publications of which 40 are original articles and 26 are review articles. Not the usual distribution of articles. It might points at an effort to leverage on small amount of data. On the other hand, of the original papers, 22 came out of Dezawa lab but 18 were authored by others. Of these 9 are products of Japanese groups and 5 are from China. Each of the following countries – Argentina, Egypt, Italy and USA (Stanford) – contributed one paper to the growing list. Certainly, this is STAP not the situation similar with the STAP swamp. More independent research is requested before we can come to a clearer conclusion.
Whenever somebody starts basing a new miracle anything on adult stem cells… I think we’re leaving the field of science and getting into the influence of politics and religion. This doesn’t mean that political and religious ideas are somehow direct influences (which wouldn’t make sense in Japan anyway), but that we can trace back the need to use adult stem cells rather than any other kind to those indirect influences. These are situations that date back many, many years and are the result of so many different factors that have fed into them that… again, we’re out of the realm of hard science here. But without them, we’d probably already have effective stem cell treatments for many chronic degenerative conditions. Would anybody really be trying to get effective treatments out of adult stem cells if we didn’t have the specter of religious and political influences hanging over our heads??
Hi Inga,
I started out including a section in my post on a similar point.
I do think this is a factor in this research.
Thanks, Paul
You need to talk to Dr. Neil Riordan about these “golden cells” that he uses in his world famous clinic in Panama. I was told his “golden cells” were MUSE cells.
Who told you that they were MUSE cells?
Those cells probably cost customers enormously more than real gold.
Agreed. I should have said things more bluntly…
Please excuse my Japanese habit to expect people to read between the lines (bad habit in science, indeed).
After reading the protocol, the culture is very tricky to say the least, depending on multiple factors (reagents, etc) not controllable until tested. How such protocol could meet the ICH requirements as regards the clinical drug supply and their quality assurance: the whole thing looks unreliable enough not to proceed to a clinical trial at all. The culture protocol must be much improved so that it will offer a stable and high enough a yield, without which the scale-up from the research lab level to clinical drug production level looks compromised to say the least.
Is the sponsor happy that the whole thing is difficult to reproduce but by the original inventor for the sake of both monoploy and secrecy, I don’t know.
But such attitude seems devoid of any sense if they are unable to bring it to an industrial scale to meet the market demand. The Tohoku U researchers would have to delegate the task of cultivating the cells since it is certainly not within their competence to grow them at a pharma production site with all the QA/GMP tasks it implies.
This is a personal view. When we look at scientific evidences on these MUSE cells, we don’t have much, if not some presentations at congresses including domestic (i.e., in Japan). The trials is in collaboration with Mitsubishi Chemical Holdings, which means the cells might have been in the private domain (secrecy agreement between Tohoku U and MCH) , or the whole thing receive a somewhat privileged handling by the government since it received the MoE grant (KAKEN) , (3 years fundamental research grant (A), No. 17H01583, 01.04.2017 to 31.03.2020, amount=42,770k Yen, approx. 393k USD). Not a humongous amount but a 3-years gov’t grant anyway.
Is the Japanese govt so much in a hurry to find a novelty in the stem cell area, despite Yamanaka said the iPS/stem cell research is in its scientific “valley period” representing the years required to ascertain the applicability of an in vitro/in vivo/ex vivo preclinical finding-base technique to a clinical trial?
I really don’t know what to say if not pointing our the sheer lack of scientific evidence supporting the portability of the therapeutic to humans, notwithstanding the lack of data supporting the well-established nature of the MUSE cells.
Now, what will happen? Only the future will tell, and hopefully before any harm is done…
Maybe there is a corporate proprietary element here. But if you look at their online protocol for MUSE, on first glance it seems like anybody could get these pluripotent cells from many tissues and cell lines: http://www.stemcells.med.tohoku.ac.jp/english/protocol/pdf/Muse_protocol.pdf.
However, digging deeper into the protocol there are many caveats and warnings (places saying “ATTENTION!” in red) about using only certain antibodies, only certain passages or cells, and so on. This makes me less confident in these cells. For example, this statement to me seems counterintuitive, “ATTENTION! Different from the subculture of mesenchymal stem cells described above, the mesenchymal stem cells must reach 100% confluence just before collecting Muse cells by FACS. If mesenchymal stem cells were under or over 100% confluence, the yield of Muse cells will be substantially decreased.” Overall, I have a lot of doubts.