8 thoughts on “STAP cell deja vu? 28 VSEL papers flagged by Bik”

  1. Gregorio Chazenbalk

    Hi Paul:
    I want to be clear and to avoid any confusion, I am only referring about the existence of Muse cells as pluripotent stem cells present in adult tissues. It is scientifically incorrect to compare Muse cells with other proclaimed pluripotent adult stem cells, because if they exist, have different characteristics than Muse cells.

    Answering your questions, I would like to address first your question how being pluripotent stem cells Muse cells do not produce teratomas upon transplantation. The definition of stem cell pluripotency relies in the ability of these stem cells to differentiate into the three embryonic germ layers. For example by CIRM “an induced pluripotent stem cell, or iPS cell, is a cell taken from any tissue (usually skin or blood) from a child or adult and is genetically modified to behave like an embryonic stem cell. As the name implies, these cells are pluripotent, which means that they have the ability to form all adult cell types”. Tumor formation (uncontrolled proliferation) coincides with pluripotency as a critical factor in determining the pluripotent capacities of both ES and iPS cells. However, in the case of Muse cells, pluripotency does not go “hand to hand” with unbridled proliferation or tumor formation, setting them apart from ES and iPS cells. The critical question is “what factors allow Muse cells to avoid tumor formation while retaining their capacity for differentiation into all three germ lineages”. Muse cells have much lower expression of the so-called ‘Yamanaka factors’ (Nanog, SOX2, Oct3/4, and cMyc) in comparison with iPS cells (> 105 fold decrease) and a very low ratio Lin28/Let7, (which is very high in iPS) and therefore abolishing this critical pathway for tumorigenic proliferation and, subsequently, cancer. Furthermore, Muse cells have low proliferative and telomerase activities and normal karyotype, as they demonstrate normal chromosome number and integrity (Simerman et al, 2014 and 2016).

    Numerous studies have already demonstrated the efficacy of Muse cells to repair damaged liver, kidney, neural, heart, and cerebrovascular tissues in different disease animal models, due to their high capacity of migration and integration into damage tissue to replenish cells and repair tissue function, driving research into potential clinical applications of Muse cells (Fisch et al, 2017, Young, 2018).

    Regarding your first question, Muse cells are indeed endogenous reparative pluripotent stem cells. Muse cells are “natural” cells present in a dormant, or quiescent state under normal physiological circumstances within the cellular niche and are activated in vitro by severe cellular stress (Heneidi et al, 2013; Gimeno et al, 2018) or highly mobilized in vivo to the peripheral blood, as demonstrated in patients with acute myocardial infarction (within 24 h of the acute phase) via sphingosine-1-phosphate receptor 2 signaling (Satake et al, 2020).

    Paul, I hope that after all these comments, your skepticism on Muse cells have been “significantly” reduced.

    Happy to answer other questions.

    Best,
    Gregorio

    1. Mariusz Ratajczak wrote in one of his reviews that various investigators are peeping into a dark room through different keyholes and are seeing/describing the same pluripotent stem cell differently. They have named these stem cells differently like MAPCs, MUSE cells, Spore-like cells or VSELs. Evidently Mother Nature will not have different sets of pluripotent stem cells for different investigators to work on. I am sure in due course scientific community will arrive at a consensus. Just like MUSE cells as pointed out by Prof Gregorio, even VSELs show much reduced expression of pluripotent markers compared to ES/iPS cells.

  2. ULTIMATELY THE TRUTH ALWAYS PREVAILS…

    Hello Paul

    The stem cell field is truly in a confused state since ES/iPS cells have failed to deliver, even HSCs failed to regenerate other tissues [PMID: 30870131]. VSELs are pluripotent stem cells in adult tissues and will regenerate when MSCs (or exosomes/ extracellular vesicles secreted by them) are transplanted. Transplanted MSCs (or exosomes/ extracellular vesicles secreted by them) act as paracrine providers to the resident stem/progenitor cells. Please be assured that the VSELs field has only become stronger since 2013 and is here to stay.

    It is crucial to develop a robust protocol to enrich VSELs from adult tissues in order to convince the scientific community and remove any doubt regarding their existence. VSELs are of very small size and do not pellet down when cells (obtained from any solid tissue by enzymatic digestion) are centrifuged at 250-600g. VSELs remain buoyant (at this speed of 250-600g) and can be enriched by further centrifuging the supernatant at 1000g. Using this straightforward and robust protocol, VSELs can be enriched from any adult tissue including pancreas, cardiac tissues, bone marrow, testes, ovary, uterus, prostate etc. [PMID: 30879243; PMID: 32303227; PMID: 31705263; PMID: 32578128; PMID: 32710237]. This enriched population of VSELs can be further characterized in details by flow cytometry and other methods. Our results contradict findings in leading journals reporting no stem cells in pancreas [PMID: 29769672] and by scRNAseq in prostate [PMID: 32355025] or ovaries [PMID: 32123174]. Scientific community tends to put the somatic mature cells and the stem cells in the same basket while processing for various experiments. This has led to several misperceptions in the field as stem cells get inadvertently discarded.

    We recently reported that disrupted VSELs biology by neonatal exposure to endocrine disruptors results in infertility, reduced sperm count and also testicular cancer-like changes in adult mouse testes [PMID: 32592162]. VSELs under normal circumstances maintain tissue homeostasis but when their function gets affected e.g., by endocrine disruptors, they initiate cancer. Cancer treatment, and to develop strategies to overcome recurrence need to target tissue resident VSELs/ progenitors.

    The sooner scientific community acknowledges existence of VSELs rather than remaining in denial and focuses on realizing their potential will be good for the progress of medical science (regenerative medicine, treating diabetes, cancer biology etc.). We are confident that Mariusz Ratajczak and his group will defend all concerns raised against their publications in due course. Scientific community needs to get convinced and brain-storm VSELs biology, why VSELs fail to regenerate lungs and other organs after COVID infection in aged patients and appreciate why transplanting MSCs ‘paracrine providers’ is showing beneficial effects in clinical studies.

    We welcome researchers across the globe to contact us virtually. We will be more than happy to discuss our protocols as Science should be done with an open mind.

    Deepa Bhartiya, PhD
    Professor and Head
    Stem Cell Biology Department
    ICMR-National Institute for Research in Reproductive Health
    Mumbai, India
    https://orcid.org/0000-0002-5384-3998

  3. Gregorio Chazenbalk

    Comment on Muse cells

    Hi Paul;

    Hope all is well.

    Finally, I decided to send you this comment on Muse cells.

    Muse cells were first discovered in 2010 from bone marrow by Dr. Dezawa’s team in Tohoku University. In 2013, our group from UCLA discovered Muse cells in adipose tissue (Muse-AT) by serendipity, after exposing fat cells to severe cellular stress (long-term exposure to the proteolytic enzyme collagenase, serum deprivation, low temperatures, and hypoxia). I remember after the publication of the MS, your quote “almost throwing everything at the fat cells but the kitchen (or laboratory) sink”.

    In contrast to ES and iPS, Muse cells have the capacity to differentiate to any cell type (pluripotency) without teratoma formation, with a high capacity of immunomodulation, homing, and tissue regeneration upon transplantation in vivo as indicated in numerous animal disease models. Based on their immunological properties, Muse cells can be used for allogenic transplantation. Currently, 4 clinical trials are on the way to be performed in Japan (Life Science, Mitsubishi) on the safety and efficacy of intravenously injected Muse cells in patients with different diseases (acute myocardial infarction, cerebral stroke, spinal cord injury, epidemolysis bullosa). The existence of Muse cells has been demonstrated not only by us but also by other 7 independent groups worldwide over the several years since their discovery. Yet, there exist others who remain skeptical today, without being aware of the properties of these cells.

    Muse cells challenge the existing paradigm of ES and iPS cells as gold standard pluripotent cell populations by introducing a novel pluripotent cell population that exists in adult tissues. Another reason for the skepticism is to confuse Muse cells with proclaimed pluripotent adult stem cells, such as MAPCs, MIAMI, VSELs, and STAP cells, among others.

    Nevertheless, based on their properties, Muse cells is a very promising candidate in the field of regenerative medicine and stem cell therapy. I can envision successful Muse cell treatment for diverse disorders in the near future.

    My question to you:
    What are your specific scientific issues that make you so skeptical on the existence of Muse cells? Maybe I and/or other scientists could address them.

    Happy Holidays
    Best,
    Gregorio

    Gregorio Chazenbalk, Ph.D.
    Professor of Obstetrics and Gynecology
    University of California Los Angeles

    1. Dr. Chazenbalk, your article about Muse cells is the most positive I have read. I have a 43 year old daughter who was diagnosed with retinitis pigmosa in 2012. We were shocked and devastated. Further testing confirmed that I carry one gene and my husband carries two. Stem cell therapy has been our only hope. She has been to Jules Stein at UCLA and is aware of studies going on at UC Irvine. Would you know if Muse cells might work for RP patients? The above new findings have left me feeling very saddened. Would you or another stem cell researcher be able to address my concerns about the negative findings of your colleagues? What type of cells would an RP patient be a candidate for? I would appreciate your reply.

      Kind regards,

      Cheryl Rossi
      chery[email protected]

    2. Dear Gregorio,
      Thanks for your comment.
      Why would the adult human body have pluripotent cells? For repair? If so, is there any proof that there are endogenous MUSE cells and they can exhibit pluripotency in vivo in people?
      If MUSE cells are real and pluripotent, why don’t they form teratoma?
      Could MUSE not exist in vivo, but are a non-naturally occurring product of a lab procedure?
      These are the kinds of questions on my mind.
      Best, Paul

      1. Dear Paul
        You raised very interesting comments on the MUSE cells but these need to be answered for VSELs as well. I am sure Gregorio will also respond but I take the opportunity to respond in the context of VSELs.

        Why would the adult human body have pluripotent cells? For repair?
        Pluripotent stem cells (VSELs) exist in all adult tissues and serve as a backup pool for the tissue-specific progenitors. They give rise to the tissue specific progenitors by undergoing asymmetrical cell divisions (ACD) whereby they self-renew and give rise to slightly bigger progenitor. We have shown ACD and differential expression of NUMB in the dividing doublets in multiple adult tissues [PMID: 30051749, Fig 5]. Thus VSELs play a crucial role to maintain life-long tissue homeostasis.

        If so, is there any proof that there are endogenous MUSE cells and they can exhibit pluripotency in vivo in people?
        Endogenous VSELs do exist and we have developed a robust and straightforward protocol to enrich them from any adult tissue. MSCs exist as pericytes in adult tissues and MUSE cells possibly exist as VSELs in vivo. Different names to the same stem cells [PMID: 24187558, Fig 1]. VSELs enriched from mouse bone marrow, besides expressing pluripotent markers, differentiate into 3 lineages in vitro. Multiple groups have shown this including our group [PMID: 28070859]. VSELs are found in tissues of all the 3 lineages and differentiate into progenitors of all lineages and even into gametes in vivo.

        If MUSE cells are real and pluripotent, why don’t they form teratoma?
        VSELs are pluripotent based on expression of pluripotent markers and by their ability to differentiate into all the 3 lineages and gametes. However, they are quiescent in nature, Ratajczak’s group has studied this and reported the underlying mechanism for quiescence [PMID: 19641521]. Mother Nature has ensured that VSELs do not form teratomas randomly in our body or when transplanted in mice because of their quiescent nature. But it is now possible to expand VSELs ex vivo in the presence of nicotinamide or valporic acid or in the presence of the small-molecule UM177 [PMID: 30653438]. Teratomas may also be developed by transplanting VSELs enriched from adult testes (neonatally exposed to endocrine disruption) … but these experiments remain to be done.

        Could MUSE not exist in vivo, but are a non-naturally occurring product of a lab procedure?
        Even MSCs are a non-naturally occurring product in vitro. MSCs exist as pericytes in vivo.

        We need to brain storm this field

        Deepa Bhartiya, PhD
        Professor and Head
        Stem Cell Biology Department
        ICMR-National Institute for Research in Reproductive Health
        Mumbai, India
        https://orcid.org/0000-0002-5384-3998

  4. Sure they look identical, that’s pretty easy for anyone to see once you point it out like that. Maybe VSELs only form in a few pre-determined shapes… you know, like chicken nuggets.

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