ESC HEART FAILURE PERSPECTIVE ESC Heart Failure 2021; 8: 2306–2309 Published online 2 March 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13256 Reparative cell therapy for the heart: critical internal appraisal of the field in response to recent controversies Thomas J. Povsic1, Ricardo Sanz-Ruiz2, Andreu M. Climent2, Roberto Bolli3, Doris A. Taylor4, Bernard J. Gersh5, Philippe Menasché6, Emerson C. Perin7, Giulio Pompilio8, Douwe E. Atsma9, Lina Badimon10, Anthony N. DeMaria11, Joshua M. Hare12, Timothy D. Henry13, Stefan Janssens14, Jens Kastrup15, Daniele Torella16, Jay H. Traverse17, James T. Willerson7 and Francisco Fernández-Avilés2* 1 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; 2Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERCV, Madrid, Spain; 3Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA; 4Center for Cell and Organ Biotechnology, Texas Heart Institute, Houston, TX, USA; 5Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA; 6Department of Cardiovascular Surgery, Georges Pompidou European Hospital, Paris, France; 7Center for Clinical Research, Texas Heart Institute, Houston, TX, USA; 8Vascular Biology and Regenerative Medicine Unit and Dept. of Cardiovascular Surgery, Centro Cardiologico Monzino IRCCS, Milan, Italy; 9 Faculteit der Sociale Wetenschappen, Instituut Psychologie, Gezondheids, Medische-Neuropsychologie, Leiden, The Netherlands; 10Cardiovascular Program (ICCC), IR Hospital de la Santa Creu i Sant Pau, CIBERCV, Barcelona, Spain; 11Sulpizio Cardiovascular Center, UC San Diego Health, San Diego, CA, USA; 12Interdisciplinary Stem Cell Institute and Division of Cardiology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA; 13The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital, Cincinnati, OH, USA; 14Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; 15 Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; 16Molecular and Cellular Cardiology LAB, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy; and 17Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, MN, USA Abstract The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients. Keywords Reparative cell therapy; Myocardial repair and regeneration; Stem cell therapy Received: 29 December 2020; Accepted: 25 January 2021 *Correspondence to: Francisco Fernández-Avilés, Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERCV, Madrid, Spain. Phone:+34 91 4265882; Fax:+34 91 586 8276. Email: faviles@secardiologia.es Introduction incumbent to critically appraise the field and formulate best practices for future work. Research on myocardial repair and regeneration has substan- tially contributed to a better understanding of cardiomyocyte biology1; however, cardiovascular reparative medicine has Light and shadows in the field been criticized in part due to modest effects in clinical trials and the perception that translation to clinically effective For almost half a century, stem cell therapy for approaches has been slow.2 The field has been further haematopoietic diseases has been a reality. The concept that affected by requests for or retractions of papers by former cell-based repair of damaged heart muscle might be possible leaders.3 As researchers, clinicians, and teachers, we felt it was introduced almost two decades ago.4 Initially, the © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 20555822, 2021, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13256 by Readcube (Labtiva Inc.), Wiley Online Library on [24/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Reparative cell therapy for the heart: critical internal appraisal of the field in response to recent controversies 2307 assumption was that extracardiac cells could engraft, mediate by the US Food and Drug Administration, the European Med- repair, and potentially replace injured tissue. Two decades icines Agency, and local regulatory bodies. We underscore later, we now have a better understanding of the molecular the necessity for rigorous evaluation of potential therapeu- and cellular mechanisms that govern cardiovascular response tics in appropriate preclinical, preferably large animal, models to injury; however, clinical studies have produced conflicting utilizing rigorous experimental and statistical methodologies. results.2 While studies of bone marrow mononuclear cells in The need for better preclinical models is not new and has patients with acute infarction have not demonstrated consis- long been felt to contribute to the immense attrition of ther- tent clinical benefit, studies with mesenchymal cells in chronic apies that appear promising but fail to lead to clinical benefit. heart failure5,6 and CD34+ cells in refractory angina7 are more It is easy to retrospectively criticize decisions to fund encouraging. Today, thanks to growing awareness that cells research that did not lead to immediately positive clinical may act indirectly to promote endogenous repair, novel and results. This speaks not to poorly conducted preclinical or exciting cell-based products are being developed. The discov- early clinical research, but to the difficulty in gleaning an un- ery that adult cells can be reprogrammed to form induced plu- derstanding of efficacy in humans with variable genetic and ripotent stem cells (iPSCs) has opened the possibility to ‘build’ epigenetic backgrounds, exposures, and broadly phenotyped human tissues. Engineered cardiac tissues, cell-derived prod- disease states when utilizing preclinical models of syngeneic, ucts (e.g. extracellular vesicles and mitochondria), and (genet- young, healthy non-medicated animals. These limitations ically) reprogrammed cells represent the forefront of current have plagued the development of therapies for various condi- cardiac regenerative approaches. tions, including heart failure with preserved ejection fraction Recently, we were shaken by the news that many papers and ischaemia–reperfusion injury, despite billions of dollars from a leading laboratory in the field were retracted.3 of research. Even with these past disappointments, clinical Misbehaviour and fraud have occurred both inside and out- need continues to drive research in these fields. While con- side the cell therapy arena.8 While these acts of misconduct clusive evidence of clinical efficacy cannot be expected from impact the perception of the entire field, these events should phase I–II studies, the experience in thousands of patients not unfairly taint the research conducted by the overwhelm- shows no evidence of significant risk with the therapies ing majority of rigorous, principled investigators. Independent studied to date, and some meta-analyses suggested a lower- scientists, sceptical about claims of cardiac regeneration, per- ing of mortality or cardiovascular risk.2,7,13 formed and published experiments with contradictory results The idea of regeneration captures the imagination in and were openly critical of now proven flawed, preclinical ways that other therapies simply do not. This has led to experiments.9 In parallel, multiple investigators questioned hope but also to hype—by scientists who overestimated the concept of regeneration and published data demonstrat- the potential and by purveyors of ‘cures’ who choose to ing improvements in cardiac function despite limited or no sell unproven therapies in minimally regulated direct regeneration.10 environments.14 This aspect of biological therapies can lead to untoward consequences. Patients lacking treatment op- tions actively seek such therapies, often in unsafe and un- regulated settings. The ‘hype’ raises unrealistic Recent criticisms, revisiting the field expectations among the public and investigators, enhancing the placebo effect in clinical trials and leading to greater Recently, the field has been beset by critical editorials and disappointment when expectations are not met. The lofty opinion pieces denouncing the National Institutes of Health goal of myocardial regeneration leads to criticism when this for wasted funding and calling for a cessation of clinical work is not achieved, yet the goals of therapy for ST-elevation in favour of mechanistic and preclinical development of ‘more myocardial infarction, heart failure, refractory angina, or promising’ approaches.11,12 These opinion pieces, some of peripheral artery disease differ. While the ability to directly which were not openly authored,11 decry the field for chang- regenerate new myocardium remains elusive, the ability to ing its understanding of the mechanisms of cellular reparative improve myocardial perfusion and/or to modulate immune- therapies (specifically, the shift from a cardiomyogenic to a inflammatory responses to injury is supported. ‘paracrine’ mechanism of action),2 the lost opportunities for funding basic research at the expense of clinical funding, and the risk to patients in clinical trials of cell therapies. These claims require a response. Steps forward Cardiovascular cell therapies entered into clinical trials with positive preclinical data supporting safety and a poten- As scientists, clinicians, educators, and recipients of public tial for efficacy from in vitro, small animal, and large animal funds beholden to the public trust, we recommit to ensur- studies. Regulators would not allow otherwise. Clinical trials ing that the field proceeds on pathways most likely to be required evaluation and approval, based on preclinical data, beneficial. The intuitive concept of reparative therapies ESC Heart Failure 2021; 8: 2306–2309 DOI: 10.1002/ehf2.13256 20555822, 2021, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13256 by Readcube (Labtiva Inc.), Wiley Online Library on [24/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2308 T.J. Povsic et al. results in far greater scrutiny, increasing our obligation to path forward when clinical needs remain significant and un- conduct well-conceived and executed preclinical and clinical met, and initial studies suggest no untoward risks. studies. 4 This (as well as other fields) might benefit from greater We note that almost half a century passed between the crosstalk between preclinical and clinical investigators. Ex- identification of specific therapeutic targets (e.g. posure of preclinical researchers and trainees to the rigour intracoronary thrombus) and the development of effective of clinical investigation would foster greater appreciation clinical therapies from these discoveries. History teaches for the demands required by regulators, while clinicians that development of novel therapies takes time. While initial might benefit from an understanding of preclinical meth- preclinical experiments fostered the hypothesis that adult odologies, furthering both arenas. stem cells might regenerate mature cardiac tissue, this 5 The heterogeneity of cardiovascular disorders should be now appears to be wishful thinking. Perhaps the most im- considered an opportunity to distinguish between differ- portant advance has been the recognition that exogenous ent therapeutic targets (i.e. chronic ischaemia vs. myocar- cells might improve cardiac function without significant en- dial loss vs. chronic dysfunction) and to generate specific graftment or differentiation into adult cardiomyocytes. Our products aimed at the repair of those different disorders. improved understanding of the mechanisms of cell therapies 6 Modestly sized clinical trials should be interpreted with should not be decried but recognized as an advancement caution. Early phase trials can inform feasibility and pro- that may lead to new approaches. Revisiting working hy- vide signals of biological effect and potency, but should potheses in light of new evidence is the essence of scientific not be interpreted simply as ‘positive’ or ‘negative’. The inquiry. Work with iPSCs and tissue engineering holds the caveats inherent to post hoc analyses of clinical trials promise of true ‘tissue replacement’, while new mechanisms should be appreciated. Significant time was lost by of cardiac regeneration (e.g. release of cell cycle check- conducting small similarly designed trials using compara- points) and modulation of the inflammasome in the heart ble products, instead of moving the field forward with ad- are now being increasingly evaluated.2 We see the following equately powered studies. as key steps forward: 7 In the clinical arena, current cell formulations have dem- onstrated some efficacy in specific conditions like chronic 1 Open dialogue, debate, and questioning results are to heart failure5,6 and refractory angina.7 Properly designed be encouraged. Scientists should acknowledge that clinical trials are warranted to conclusively address the ef- adult ‘stem cell’ formulations, to date, do not directly lead fect of cell therapy in these conditions. to cardiomyocyte regeneration in the human heart. 8 Fresh approaches challenging prevailing dogma should be 2 Enthusiasm was genuine, but at times excessive, leading to fostered by funding and promotional mechanisms that re- hasty translation of basic research. We should boost ward innovative unconventional approaches and opinions. greater interaction between basic and clinical investiga- We urge changes to funding review processes that support tors, both to aid transition of promising approaches to and encourage research the runs counter to ‘conventional’ the clinic in a timely manner and to encourage and facili- ideas. tate ‘bedside-to-bench’ studies. 3 We should recognize the complexity of preclinical research. The first two decades of research into the regenerative prop- Standards of rigour analogous to those routinely used in erties of the heart have brought both failures and successes. clinical studies (blinding, randomization, trial registration, It would be an error to be dismissive of the progress made. multicentre design) should be adopted. While generating We should remain dedicated to the field and confident that more relevant (older, sicker, medicated) large animal this line of investigation contains promise to substantively models of human disease remains a laudable goal, for many help patients with a variety of cardiovascular conditions, in- disease states, this remains elusive; thus, cautious carefully cluding orphan and undertreated populations for whom designed human experimentation may represent the best there are no other palliative or curative alternatives. References 1. Eschenhagen T, Bolli R, Braun T, Field LJ, 2. Braunwald E. 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