• Cryopreservation of mesenchymal stromal cells can attenuate clinical immune effects
    As Jacques Galipeau reported in conferences and in the paper, cryopreservation could negatively affect therapeutic “immunomodulatory value” of mesenchymal stromal cells (MSC). There was no independent confirmation of Galipeau’s findings, and many MSC product developers remained skeptical. This week, Katarina Le Blanc published a report, which supports Galipeau’s conclusions and provides more insight into potential clinical value of this phenomenon. Let me just say – this paper could change the field! Le Blanc concluded that freeze-thawed human MSC compared to […]
  • Cells Weekly – August 31, 2014

    by Alexey Bersenev on September 1, 2014 · 0 comments

    in notes

    Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Please give us feedback and send links to interesting news!

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    1. RIKEN’s interim report on STAP reproducibility
    RIKEN fails to reproduce STAP as per interim report, released on August 27. Histoshi Niwa is leading STAP reproducibility efforts with help of Haruko Obokata. He noted on presse-conference: “No clear signs of the STAP phenomenon could be observed so far in 22 experiments”. Obokata will keep trying until next March, when final results will be announced.
    A big part of RIKEN report describes re-organization of institution:

    On 27 August, RIKEN said that the centre would be renamed, and its number of laboratories cut. It was not clear how many of its 540 staff would lose their jobs, if any. Masatoshi Takeichi, who has led the CDB since it was founded 14 years ago, will step down.

    2. Embryonic stem cell trial for spinal cord injury is re-started
    The most exciting news of the week came from Asterias Biotherapeutics. FDA approved their clinical trial, which will assess embryonic stem cell-derived neural cells in cervical spinal cord injury. Asterias completed acquisition of Geron’s stem cell assets at the beginning of 2013. Cell product in new trial will be the same (as Geron’s one), but cell dose will be escalated up to ten times.

    Selection of the clinical trial sites is well underway and the Company expects to begin patient enrollment during the first quarter of 2015.

    The new clinical trial differs from the original clinical study in that doses up to 10 times higher will be tested. In addition, the trial will focus on patients with neurologically-complete cervical spinal cord injuries.

    The results of the Phase 1/2a clinical trial are expected to provide support for a Phase 2b expansion study that will be conducted to more thoroughly demonstrate safety and efficacy of the product.

    3. Tributes to Yoshiki Sasai
    Stem cell community continues to pay tributes to Yoshiki Sasai – a scientist, who committed a suicide on August 4. Great popular article was written by Mo Costandi:

    Sasai believed that self-organisation only emerges from populations of a certain size. “This kind of thing can only be seen in groups of about 1,000 to 100,000 cells,” he said. “At this level, cells can be directly democratic, and don’t need a special governor or president to orchestrate them. In a village of several hundred, the people can probably get together and decide what to do, but a country would be a total mess without a government.”

    Stefano Piccolo wrote Sasai’s obituary for Development journal:

    Hopefully, Yoshiki’s ‘eyes-in-vitro’ will help treating blindness in the future. But whatever the translational legacy of his work, he was certainly a visionary scientist, who opened our eyes to the wonders of developmental and stem cell biology and its potential for mankind.

    Paul Knoepfler posted “community tribute” on his blog. You can leave your name under the tribute.

    One more tribute I’d recommend to read – by Enrique Amaya on Xenbase.

    4. First approval of bioprinted medical implant by FDA
    On August 19, Oxford Performance Materials announced approval the first bioprinted medical implant in US:

    …it has received 510(k) clearance from the FDA for its 3D printed OsteoFab® Patient-Specific Facial Device (OPSFD).
    OPM’s facial device is the first and only FDA cleared 3D printed polymeric implant for facial indications, and follows FDA clearance of the first and only 3D printed polymeric implant, OPM’s OsteoFab Patient-Specific Cranial Device, which was granted in February 2013.

    Multiple cases of implantation bioprinted materials have been described in the last 2 years worldwide. However, this is first official approval by FDA for implantation of “something 3D printed” in human body. Important milestone!

    5. Use of iPS cells for engineering of whole lung
    Harald Ott’s lab from Harvard published important study on potential usability of iPS cells for engineering of  lung from decellularized matrix. Two novel and improved methodological approaches were used by the authors: (1) “constant perfusion biomimetic culture” and (2) in vivo graft maturation:

    Cells cultured on decellularized lung slices demonstrated proliferation and lineage commitment after 5 days. Cells expressing Nkx2.1 were identified at 40% to 60% efficiency. Within whole-lung scaffolds and under perfusion culture, cells further upregulated Nkx2.1 expression. After orthotopic transplantation, grafts were perfused and ventilated by host vasculature and airways.

    6. Addressing donor variability in translation MSC research
    Folks from Democratizing Cell Technologies blog posted great piece on importance of assessing donor variability in development of mesenchymal stem cell-based therapies:

    Even with the consensus amongst the scientific community that donor variability is a critical component to address for the success of cell-based therapies, the majority of scientific publications still use just a single donor to support new discoveries. Clearly, to ensure the robust production of functional MSC products over a range of applications, experiments should be conducted and systems validated with MSCs from several donors. It has been reported that best practices to qualify a manufacturing process should include “at least 3-5 donors”, and it is likely that proper validation will require many more.

    Highly recommended!

    7. Challenges in regenerative medicine translation – interview with Jennifer Elisseeff
    Recently I was enjoying reading an interview with Jennifer Elisseeff, conducted by Methuselah Foundation. Elisseeff is a Director of the Translational Tissue Engineering Center at Johns Hopkins University School. Interestingly, she spoke not only about regenerative medicine, but current challenges for young investigators in academia:

    …I’m on a panel, so I’ve seen how they run, and it’s really impossible to choose between the top X percentage of grants. They’re all great. So you end up just nitpicking, and you lose a lot of good science in the process. Then those researchers have to write up another X number of grants because they didn’t receive money for that very good grant to start with.
    Overall, it’s just a very destructive environment for science and future innovation. It’s particularly challenging for junior faculty members, but it’s not a walk in the park for anybody. I often wonder how many hours and how much science we lose because of this.

    8. HIV escape mechanism can circumvent CCR5-knockout strategies
    After success of single case (“Berlin Patient”), many research groups around the world are trying to modify CCR5 receptor to inhibit entry of HIV into immune cells. However, new HIV escape mechanism was describe in the letter to NEJM:

    The genotypic analyses of HIV-1 variants in this patient showed a shift from a dominantly R5-tropic HIV before stem-cell transplantation toward an X4-tropic HIV after transplantation. This shift of tropism was probably driven by transplantation with stem cells homozygous for the CCR5 delta32 mutation. This case highlights the fact that viral escape mechanisms might jeopardize CCR5-knockout strategies to control HIV infection.

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    10 new companies to watch – part 3

    by Alexey Bersenev on August 29, 2014 · 0 comments

    in RegenMed digest

    Ten Companies to Watch became very popular series on StemCellAssays. Thanks for your interest! This is a fresh list of the most interesting (in my opinion) companies, where I considered and included some of your suggestions. The criteria for my pick are the following:

    • Related to stem cell research, regenerative medicine, cell therapy, gene therapy field (therapeutic, tools, reagents, service);
    • New (0-5 years of existence) or relatively new, but under-appreciated and widely unknown;
    • Very unique approach/ new platform

    *******************
    1. Bell Biosystems
    Company creates synthetic cell organelles – magnetic nanoparticles. Cells with these organelles could be easily tracked and manipulated in vivo. Very cool and unique approach!

    2. Human Longevity Inc
    Very new startup, dedicated to studying aging and “hacking” human longevity by using means of genomics, microbiomics, proteomics, informatics and stem/ cell therapy technologies. Backed up by “big names”, such as Craig Venter and Robert Hariri, company launch made a big buzz in mass media. Stem cell/ cell therapy part of company will utilize Hariri’s expertise in placenta-derived stem cell products.

    3. Asterias Biotherapeutics
    A public company, subsidiary of BioTime. Last year Asterias completed acquisition of Geron’s stem cell assets. This year they released safety results of halted Geron’s embryonic stem cell-based trial and got approval of FDA to proceed with new trial in spinal cord injury patients.

    4. Emulate Inc
    Very new spinoff from Harvard’s Wyss Institute for Biologically Inspired Engineering. Emulate is aimed to commercialize “Organs-on-Chips” platform for multiple applications. Strong scientific background and market demand for such technology, could promise a great future to the company.

    5. Lung Biotechnology
    A subsidiary of United Therapeutics Corp., which recently entered to the business of humanized organs transplantation. In collaboration with Synthetic Genomics Inc XenoLung project will be dedicated to engineering of pigs with humanized lungs for transplantation.

    6. SighRegen K.K./ Healios
    SighRegen is joint venture of Japanese company Healios, which will commercialize the first iPS cell-based therapy at RIKEN.

    7. Orgenesis
    The first company which utilized direct cell reprogramming (transdifferentiation) for therapeutic purpose. The technology involves conversion of liver cells into pancreatic islet-like cells by using gene-modification with transcription factor (PDX-1). Recent deal with contract cell manufacturer MaSTherCell brought Orgenesis very close to the first clinical trial.

    8. Cytonome
    Company creates new generation of cell purification/ sorting systems. Clinical sort-on-chip technology has great commercial potential in cell therapy. The first validation study for GigaSort was recently published.

    9. Stem Cel
    Italian company which develops “new way of cell sorting”. The company is aimed to provide an alternative to traditionally used FACS and MACS technologies at lower cost with clinical application. The prototype in development called “Celector”.

    10. Sistemics
    UK-based company, which develops a new way to assess identity and potency of cellular therapeutic products. In order to do so, company utilizes miRNA signatures of cell products. Once unique miRNA profile is identified, it could be used as a tool for cell product characterization and/ or potency assay.

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    Parabiosis is an experimental model where two animals joined together surgically to create shared circulation system. Heterochronic parabiosis – joining two animals of different age – is used in stem cell and aging research for the last few decades. Very recent studies, based on parabiosis model, unveiled a specific factor in young mice blood – GDF11, which can “rejuvenate” aged muscle and brain tissues. About a dozen of such “rejuvenation” studies (usually linked to few groups in Harvard and Stanford) made a big slash in mass media and captured a lot of attention. This year, parabiosis-based aging research finally made a big “translational leap”. First, Harvard’s group claimed a patent for GDF11 and potential commercialization. Second, Wyss-Coray from Stanford started a company “Alkahest” and moved to the first clinical trial to assess “young plasma” in Alzheimer’s disease patients.

    Historically, heterochronic parabiosis techniques was used for more than 50 years to study aging and has been controversial. On the one hand, methodology is technically difficult to perform, associates with high animal mortality and inflammation. On the other hand, the technique has a great value in aging and immunology research. If you look at history of interest to parabiosis model by number of publications, you can see spike in 1970s and decline in modern time:

    (click picture to enlarge)

    Wyss-Coray noticed in his review that parabiosis model was “shunned in many countries”. Probable reasons for it were (i) requirements for special surgical technique and (ii) ethical consideration about “non-humane” animal care and suffering. Interestingly, all these recent “big studies” have no criticism whatsoever. A week ago I came across very interesting critical piece about the last Wyss-Coray’s study. This study is a scientific justification for upcoming Stanford’s Alzheimer’s trial. Reinhard Stindl made a few good critical points about this study – first, he said cell transfusion effect was not ruled out; second, “cognitive boost” testing has a weak statistical power. Finally, he wrote:

    Let me just add here that I disapprove of experiments like parabiosis, since human suffering from diseases can never be an ethical basis for this kind of torture of cognitive animals.

    Interestingly enough, the piece appeared in the new “open peer-review” platform “the Winnower“. The author made an attempt to submit his comment to Nature Medicine, but got rejected.

    I think, the interest to heterochronic parabiosis model in aging and stem cell research will continue to decline. Despite its potential value, this model is complex and not “fine tuned”. More likely, mix of many factors in young blood plays “rejuvenation role” – cells and proteins. It will require a lot of efforts to identify some of “enigmatic youth factors”. We should not underestimate role of monocytes and hematopoietic progenitors. The model is not robust, not rapid, not cheap, not easy to perform. It could not be used as routine screening assay in industry. What can replace this model in the future is “human-on-chip” platform. Artificial circulation system could be created between few “organ-on-chip” modules. This system could be “fine tuned”, because you can control every parameter. We can re-create “young blood circulation” and study its influence on any type of brain cells. This system could be scalable, robust and fast.

    What do you think about parabiosis model? Does it have a future? Is it ethical? Please comment!

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    Methods and Protocols Digest – August, 2014

    by Alexey Bersenev on August 25, 2014 · 0 comments

    in methods,protocols

    Methods and Protocols Digest is a collection of links to the methodological articles, freely available online. Please share your protocol with community!

    FEATURED:

    Mesenchymal stromal cells
    Comparison serum-free media Mesencult XF and FBS for MSC culture (Stem Cell Res Ther)
    CD146+ MSC isolation from human umbilical cord and telomere analysis (F1000 Research)

    Neural cells
    Xeno-free derivation of neural stem cells from CD133+ ES cell progeny (Stem Cell Res)
    Electrical maturation of neurons derived from human ES cells (F1000 Research)
    3D microarray platform for human neural stem cell differentiation and toxicology (Stem Cell Res)

    Reprogramming
    Reprogramming of various cell types to a beta-like state by 3 transcription factors (PLoS ONE)
    Reprogramming of human amniotic cells to neural rosettes for sentinel assays (PeerJ)
    Hepatocyte induction of umbilical cord-derived mesenchymal stromal cells by one factor (PLoS ONE)

    Cardiac repair
    Isolation and characterization of mouse Sca1+ cardiac progenitors (BMC Biotechnol)

    Pluripotent stem cells
    Generation of cartilage from pluripotent stem cells – review (Tiss Eng Part B)
    Embryoid body formation from human pluripotent stem cells in E8 media (StemBook)

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    Cells Weekly – August 24, 2014

    by Alexey Bersenev August 24, 2014 notes

    Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! A couple of announcements: * I’ve gotten few requests for access to public dataset “Stem cell therapeutic products on the market“. Apparently, the link didn’t allow to view it by anyone. Now the link should work – find it here. Please let me know if you still have problems with access. Table […]

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    Lecture: James Shapiro – Cell transplant therapies for diabetes

    by Alexey Bersenev August 23, 2014 lectures

    James Shapiro is a pioneer of islet transplantation for treatment of diabetes. He is the author and driving force behind famous Edmonton Protocol, which was developed in the late 1990s at the University of Alberta Hospital. In this video he is talking about the history of islet transplantation for treatment of diabetes, clinical results, challenges and new prospects. Importantly, he mentioned that trials in the final (phase 3) stage and expressed a hope for obtaining of BLA (as a “drug”) […]

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    Role of adult stem cells in organ regeneration is overstated

    by Alexey Bersenev August 21, 2014 other adult stem cells

    Today, the dogma about regeneration of adult organs from stem cells still prevails. However, the series of studies from last year has challenged our current understanding of tissue regeneration in adults. Two more studies, published last week, added “one more nail in the coffin” of current dogma. Both studies utilized lineage tracing and genetic analysis in the models of liver injury. Johanna Schaub demonstrated that none of “liver stem cell” candidates contributed to hepatocyte replenishment in chronic liver injury: In […]

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    Clinical cell processing news – part 4, 2014

    by Alexey Bersenev August 19, 2014 clinical lab

    Clinical Cell Processing News is a series about new protocols, products and techniques for clinical-grade cell processing and manufacturing. Cell processing devices, cultureware, bioreactors, GMP-grade reagents, cell separation techniques. This series is posted every 2 months. Follow us! FEATURED: Validation of clinical sort-on-chip system GigaSort for regulatory T-cells sorting (Cytotherapy) This study presents a technology adapted to regulatory requirements for clinical cell purification and that achieves high throughput and cell-friendly conditions by use of a microfluidic chip with 24 parallel […]

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    Cells Weekly – August 17, 2014

    by Alexey Bersenev August 17, 2014 notes

    Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. Suicide notes of Yoshiki Sasai Japanese stem cell scientist Yoshiki Sasai committed suicide two weeks ago. He left few suicide notes, one of which was addressed to Haruko Obakata (the author of STAP papers) and released for public right after tragedy. It said: “Be sure to reproduce STAP cells”. This week, […]

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    How publisher can destroy public trust in science

    by Alexey Bersenev August 16, 2014 notes

    One side of whole STAP story was poorly discussed in media and among scientists – the role of Nature magazine. Some of us, including myself, thought that publisher (namely Nature Publishing Group) should make a decision to release STAP papers peer reviewers comments and editorial correspondence. We believed that it will benefit the process of scientific publishing and science in general by learning from mistakes. Apparently, Nature’s editorial noticed this request and editor-in-chief Philip Campbell replied: Some say that the […]

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