Regenerating the field of cardiovascular cell therapy

In 2001, I received an email from Nature requesting a review of an intriguing paper that would launch the field of cardiovascular cell therapy.

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The claims were astounding, almost unbelievable, but the data appeared extensive, internally coherent, and had widespread, direct positive consequences for patients with advanced forms of heart disease. After multiple revisions, which were quite responsive, I became sufficiently persuaded, along with the other reviewers, to recommend acceptance, particularly given the potential clinical impact.  Of course, I had no way of knowing that 18 years later Nature Biotechnology would commission me to comment on the retraction of this study (10.1038/35070587) along with 30 other publications.  

Over the ensuing years, I had become increasingly skeptical of this initial paper by Orlic et al, as the trans-differentiation of bone marrow cells to other non-hematopoeitic tissues was reported to be artifactual.  In 2004, I was asked again by Nature to write a N&V (10.1038/nature02500) to accompany a trio of papers (10.1038/nature02446; 10.1038/nature02460; 10.1038/nm1040) that provided independent, rigorous, and, in my view, unequivocal evidence to refute the claims that unfractionated bone marrow could robustly trans-differentiate into differentiated cardiomyocytes.  The reason for the discrepancy was unclear, but our lab and others had noted a high non-specific background in immunostaining studies, which were central to the Orlic study. At the time, my own lab had begun to rely on genetically based lineage tracing to track cell fate to avoid this problem, so my thinking at the time was that this controversy might relate to  artifactual background staining. Now it appears that this technical flaw, and other errors of scientific misconduct, have lead to the retraction of an entire body of work that includes the report of putative adult resident heart muscle stem cells, that are distinct from embryonic heart progenitors (10.1016/S0092-8674(03)00687-1).  While these retractions triggered brief reports in the mainstream lay and scientific media, the duration and magnitude of the scientific misconduct called for a rational, analytical, and comprehensive retrospective.  Hopefully, the field could move beyond this setback by identifying preventive measures.  Also, it would be timely to emphasize the exponential advances from multiple independent laboratories world-wide in cardiovascular stem cell biology and novel approaches to promote heart regeneration.

The resulting NBT Perspective  (10.1038/s41587-019-0042-1) represents the collective, consensus view of the authors, who take complete ownership of the views represented in the piece.  The authors comprise those who have worked in the CV stem cell field for many years, a pharma scientist/executive/SVP who is spearheading an active search for new approaches to heart regeneration, a leading neuroscientist who developed a quantitative approach to measure heart muscle turnover in the normal and injured human heart, and world-class stem cell scientists who have direct knowledge of the events which transpired during the extensive review of the retracted studies. I would like to note that this blog represents my personal view and I am solely responsible for the comments to follow.  

Our own work has focused largely on defining heart progenitors and the paracrine pathways which drive their cell fate during cardiogenesis, using genetic tools and a combination of mouse, human, and most recently in NHP model systems.  While I have been working closely with biotechnology on a wide array of projects (recombinant protein/antibodies, modRNA, ASOs, gene therapy, etc.) over three decades, my own lab is a relative ‘new-comer’ to cell based therapy.  Only recently have we begun to attempt to translate our work on embryonic heart progenitors towards cell based therapy. One of the main reasons for this late entry has been my firm belief that the clinical goal of heart regeneration is relatively easy to rationalize, but difficult to realize.  A marked underestimation of the challenges of cell-based therapy could be viewed as largely responsible for the rapid onset of clinical cardiac cell therapy studies that followed the Orlic et al publication.  The limited scope of the NBT piece did not allow an opportunity to fully emphasize this point, and I have taken the liberty of outlining my personal views of the key issues to unlock the full potential of cardiac cell therapy 

The identification of the optimal cell type has clearly been the initial road block and remains a major issue.  Populations of diverse, differentiated, immature cardiomyocytes from human pluripotent stem cells represent the current front-runner, and are poised for clinical studies by leading laboratories in California, Germany, Japan and elsewhere. However, it remains unclear whether specific cardiac cell types (ventricular), or their respective progenitors are optimal from a biotechnology standpoint (scalability, CMC/batch-to-batch variation, cost of goods, etc.) and onset of clinical side-effects (arrhythmias). Migration, controlled proliferation, and in vivo grafting need to be optimized and coordinated with defining the optimal developmental time window for harvesting heart progenitors or cardiomyocytes during hPSC cardiogenesis.  In vivo delivery remains a major issue, and the development of next-generation “smart devices” that maximize delivery and grafting of the payload would seem warranted.  Until recently, little attention has been paid to the immunobiology of transplanted hPSC derived cardiomyocytes, as it may be difficult for patients with advanced CHF to tolerate full bore immunosuppression.  Regulatory agencies are likely to demand careful, periodic monitoring to track the injected cells that may require new imaging technologies to track the cell payload that may leak out to other organ systems.  Finally, in my view, there is a need to explore and carefully define the optimal patient subset for cell-based therapy and to tailor animal models that have fidelity to clinical reality.  Post-MI advanced CHF is decreasing in the US and most developed nations with the advent of acute interventional therapy and a host of aggressive medical therapies (statins, beta-blockers, ACE inhibitors, etc.).  It may be time to extend studies to the setting of distinct forms of cardiomyopathy, including CHF with normal ejection fraction that is a major unmet need in our aging population.

While collectively the above problems appear daunting, I remain confident that a science driven approach to optimize each of these steps will ultimately lead to clinical reality for heart cell based therapy for a wide variety of cardiovascular patients.  In my view, this will require close, real-time collaboration between leading stem cell biologists and physicians in academia, as well as a concerted. long-term effort from large pharma and the biotechnology private sector.  In any event, rethinking how academia and the private sector work together is long overdue.  Not only the fate of the cardiac cell therapy field is at stake, but so are the prospects for a growing population of patients with heart disease in this century.

Kenneth R. Chien

Professor, Karolinska Institutet

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