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Regenerating the Field of Cardiovascular Cell Therapy

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Regenerating the Field of Cardiovascular Cell Therapy PERSPECTIVE https://doi.org/10.1038/s41587-019-0042-1 Regenerating the field of cardiovascular cell therapy Kenneth R. Chien1,2*, Jonas Frisén1*, Regina Fritsche-Danielson3*, Douglas A. Melton 4,5*, Charles E. Murry 6* and Irving L. Weissman 7* The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven. Over the past 18 years, a generation of physicians and scientists has lost years chasing these studies, and patients have been placed at risk with little scientific grounding. Funding agencies invested hundreds of mil- lions of dollars in irreproducible work, and both academic institutions and the scientific community ignored troubling signals over a decade of questionable work. Our collective retrospective analysis identifies preventable problems at the level of the editorial and peer-review process, funding agencies and academic institutions. This Perspective provides a chronology of the forces that led to this scientific debacle, integrating direct knowledge of the process. We suggest a science-driven path forward that includes multiple novel approaches to the problem of heart muscle regeneration. he ultimate goal of regenerative medicine is to repair organs isolated the first lines of human embryonic stem cells (hESCs)5. Less and tissues after life-threatening injury or disease. But for discussed nowadays is another prevalent hypothesis of the era: the Tregenerative medicine directed to the heart, the field of car- notion that adult stem cells are highly plastic and, when transplanted diac cell therapy itself cries out for ‘regeneration’—damaged as it into new environments, can ‘transdifferentiate’ into cells that belong is by the retraction of over 30 papers touting the promise of puta- to their new host site. In the early 2000s, several reports posited the tive adult blood-forming or heart endogenous stem cells for healing transdifferentiation of bone marrow hematopoietic stem cells into myocardial injury1. Given the crushing medical complications of brain, lung and liver, for example6–10. Although these studies were patients with end-stage heart failure, the marked increase in preva- subsequently disproven (brain and lung) or shown to result from lence, and the severe limitation of donor hearts for transplantation, cell fusion (brain and liver)11,12, they seeded the ‘anything is possible’ the retracted studies, published by Anversa and colleagues from zeitgeist that emerged. 2001 onward, created excitement among patients, physicians and Delving a bit deeper, it was clear at the time that these iconoclastic scientists. At the time, outside of blood stem cell therapy, cardiac studies ran counter to several decades of work in hematopoiesis and regeneration may have been the most compelling case for translat- transplantation biology. Blood or hematopoietic stem cells (HSCs) ing fundamental advances in stem cell science into clinical prac- had been prospectively isolated and shown to self-renew HSCs as tice. Consequently, after dozens of clinical studies and/or trials and well as to give rise to all blood cell types for life. In the 1990s, HSC almost two decades of largely fruitless work, the degradation of transplants to replace bone marrow, mobilized peripheral blood or public confidence in this field is palpable, along with the dashed umbilical cord blood transplants were tested in experimental sys- hopes of millions of patients worldwide with end-stage heart dis- tems and in autologous transplant clinical trials (for a review, see ease. At this pivotal moment for the field of regenerative cardiovas- ref. 13). In 2005, a study tracing HSCs transplanted into mice found cular medicine, it is timely to bring a clear and frank retrospective no evidence that HSCs can transdifferentiate into tissues other than analysis of the ontogeny of this biomedical tragedy. Our sole aim blood cell types14. Even in parabiotic mice, with linked circulations here is to help avoid a repeat, in any area of regenerative medicine, and mixing of blood cells, a 2002 study did not observe appreciable and to chart a corrective course for cardiac cell therapy. transdifferentiation of circulating HSCs into nonhematopoietic tis- sues15. Nevertheless, several papers were subsequently published A flawed idea takes hold that countered those data and claimed that HSCs can normally How did the proposition that blood-forming stem cells could trans- transdifferentiate to many distinct cell types. differentiate to most or all nonblood tissues take hold? This field The publication of these reports represents a failure of many of dreams has its roots in the late 1990s—a remarkably productive entities to take the advice of stem cell biologists who were experts in time in stem cell biology. Dolly the sheep was cloned by somatic cell the field. These entities include the investigators who claimed that nuclear transfer by Wilmut and colleagues2, proving that an adult HSCs are plastic and can assume other tissue fates after injection cell could be reprogrammed to totipotency3,4, and Thomson’s group5 into animals16. They include high-impact journals that accepted 1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. 2Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 3Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden. 4Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. 5Howard Hughes Medical Institute, Chevy Chase, MD, USA. 6Departments of Pathology, Bioengineering and Medicine/Cardiology, Institute for Stem Cell and Regenerative Medicine, Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA. 7Institute for Stem Cell Biology and Regenerative Medicine; Ludwig Center for Cancer Stem Cell Biology and Medicine; Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA. *e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected] 232 NATURE BIOTecHNOLOGY | VOL 37 | MARCH 2019 | 232–237 | www.nature.com/naturebiotechnology NATURE BIOTECHNOLOGY PERSPECTIVE Pro 3 2 4 10 12 1 5 67 8 9 11 13 14 15 16 17 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Con 1 576 8 10 12 14 15 16 17 2 9 11 13 18 3 4 References Human-based studies Clinical trials n o Pr Co 1: Orlic et al., Nature. 200121 1: Murry et al., Nature. 200427 2: Beltrami et al., N. Engl. J. Med. 200118 2: Balsam et al., Nature. 200428 3: Leri et al., Proc. Natl Acad. Sci. USA. 200119 3: Nygren et al., Nat. Med. 200429 4: Strauer et al., Dtsch Med. Wochenschr. 200124 4: Chien et al., Nature. 200430 5: Orlic D et al., Proc. Natl Acad. Sci. USA. 200121 5: Laugwitz et al., Nature. 200531 6: Quaini et al., N. Engl. J. Med. 200220 6: Janssens et al., Lancet. 200658 7: Strauer et al., Circulation. 200223 7: Moretti et al., Cell. 200632 8: Beltrami et al., Cell. 200335 8: Pouly et al., J. Thor. Card. Surg. 200846 9: Oh et al., Ann. NY Acad. Sci. 200442 9: Zhou et al., Nature. 200833 10: Wollert et al., Lancet. 200425 10: Bergmann et al., Science. 200955 11: Dawn et al., Proc. Natl Acad. Sci. USA. 200537 11: Bu et al., Nature. 200934 12: Linke et al., Proc. Natl Acad. Sci. USA. 200536 12: Senyo et al., Nature. 201347 13: Assmus et al., N. Engl. J. Med. 200626 13: Nowbar et al., BMJ. 201459 14: Hatzistergos et al., Circ. Res. 201038 14: van Berlo et al., Nature. 201450 15: Bolli et al., Lancet. 201144 15: Sultana et al., Nat. Commun. 201552 16: Makkar et al., Lancet. 201245 16: Wollert et al., Eur. Heart J. 201757 17: Kajstura et al., Circulation. 201256 17: Vagnozzi et al., Circulation. 201853 18: Oransky et al., STAT. 20181 Fig. 1 | Timeline of fundamental findings and preclinical outcomes supporting or contradicting the notion of cardiac stem/progenitor cell therapy. Human studies and clinical trials are indicated with icons. papers claiming transdifferentiation of HSCs or blood cells to heart into a clinical trial that was completed and published the following or brain or intestines or skeletal muscle, despite multiple negative year23 (Fig. 1). The simplicity and purported robustness of the initial reviews by stem cell experts. Some of these journals simultaneously mouse work, coupled with few clinical regulatory barriers for autol- rejected papers showing the first prospective isolation of human ogous transplantation beyond a local institutional review board, fetal brain stem cells, which were restricted to regenerating the tis- along with the documented efficacy of acute intervention (angio- sue from which they were obtained, while publishing a claim that plasty) during acute myocardial infarction, quickly led to anecdotal brain stem cells make blood17. Culpable entities also include fund- and large-scale clinical studies worldwide24–26, several of which were ing agencies that awarded large grants to basic and clinical scien- published in major medical journals. tists who proposed that regeneration in humans can be achieved by Meanwhile, a number of investigators had difficulty reproducing remarkably simple strategies such as putting bone marrow cells into several of the Anversa group’s original experimental findings. Three injured tissues and seeing what sticks. papers published in 2004 provided direct, unequivocal evidence that the transplanted bone marrow did not transdifferentiate into A short and unfortunate history cardiac muscle27–29 as initially reported (Fig. 1). While the basis for Pathologists had long taught that the heart is among the least regen- this discrepancy was not clear at the time, it was noted that the initial erative organs in the human body, a view based on centuries of clin- findings were based entirely on immunostaining to show the inter- ical and experimental observations.
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