14 thoughts on “Dubious MUSE cells are in 4 Japanese stem cell trials”

  1. 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.

      1. Umberto Galderisi

        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.

  2. @Paul Knoepfler

    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

    1. 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

  3. 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.

  4. Inga Andersdotter

    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??

  5. 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.

  6. 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.

  7. 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…

    1. 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.

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