A Time to Press Reset and Regenerate Cardiac Stem Cell Biology

Abstract

In 2001, a research team published 2 high-profile reports 1,2 suggesting that bone marrow could regenerate the heart and new myocytes are formed in the human heart at a substantial and surprising rate. The articles upended existing dogma and contradicted years of rigorous analysis. Researchers struggled to reproduce the findings with limited success, and Nature took the unusual step of publishing 3 separate negative studies in 2003 and 2004 suggesting that bone marrow could not regenerate myocardium. [3][4][5] Other researchers found that new myocardial cells in the adult heart are formed only rarely, if at all. 6 Nevertheless, a cadre of researchers continued to publish work supporting the possible existence of bone marrow-derived cardiac stem cells and received millions of dollars from federal agencies and foundations for their ongoing research. Unchecked optimism by many in the cardiology community led to rapidly initiated clinical trials despite the controversy, and over the next decade, thousands of patients received cardiac infusions of putative stem cells both within and outside of clinical trials sponsored by the National Institutes of Health (NIH), costing taxpayers additional millions of dollars. When it became clear that bone marrow does not contain cardiac stem cells, researchers reported the existence of a different, resident cardiac stem cell within the heart itself that could regenerate the myocardium. 4 When subsequent studies failed to show myogenic differentiation of these putative resident stem cells in vivo, yet another theory was generated to defend the purported benefit of injecting these nonstem cells into the heart; perhaps they were secreting a beneficial paracrine factor that caused the heart to regenerate, although the nature of such a factor was elusive and the benefits transitory at best.All along, outstanding scientists were publicly challenging the claims of miraculous cardiac stem cells, and they published thorough and carefully executed studies documenting the virtual absence of cardiac regeneration from stem cells (<0.01% per year 7 ). Claims of lung stem cells with cellular markers similar to those of the putative cardiac stem cells met with widespread skepticism, despite the original publication of their existence. 8 Last month, it was learned that an ongoing investigation at Harvard and Brigham and Women's Hospital concluded that 31 articles should be retracted. 9 It is still not known which 31 contain serious enough errors to induce Harvard to make this public announcement. Last year, Harvard and Brigham and Women's Hospital agreed to pay the NIH $10 million to settle concerns associated with their funding of the involved laboratories. While some degree of cardiac regeneration, likely resulting from proliferation of existing myocytes, Opinion EDITORIAL

Characterization of Human Cardiac Mesenchymal Stromal Cells and Their Extracellular Vesicles Comparing With Human Bone Marrow Derived Mesenchymal Stem Cells

“…Recently, a decision has been made on an issue concerning the regeneration of CS/CPCs, especially c-kit ＋ cells (6, 8, 26): 31 papers from a researcher at the Harvard lab studying the role of c-kit ＋ cells as potential CS/CPCs were retracted http://bmbreports.org BMB Reports because of 'the inclusion of fabricated and/or falsified data' and the ongoing clinical trials involving these cells were paused (27,28). Many scientists say that it is time to reset the putative CS/CPC research, although there are some researchers saying that c-kit ＋ cells are still valid for further analysis of regeneration effects based on some animal study results (28,29). However, it was known that c-kit ＋ cells are only a minor fraction of the whole CDC from previous reports (22), and these cells barely differentiate into cardiomyocytes.…”

Restoring public trust in scientific research by reducing conflicts of interest

“…An absence of oversight often leads to investigators participating in clinical studies that lack rigor in trial design, data collection, and/or are prone to overinterpretation of "encouraging" data buried in clinical endpoints that were not prespecified. In this regard, two recent reviews on the use of cardiac stem cells for regenerating heart muscle pointed out that recent stem cell trials were rife with COIs (7,8). For example, studies published in high-impact journals by investigators having an equity interest in the sponsoring entity or in a collaborating or contributing company reported salutary benefits of cell therapy in clinical trials that Conflict of interest: AMF is the scientific founder and has significant equity in and serves as a director of Renovacor Inc., which has in-licensed pending patents 15/115,807, 15/753,003, and 62/764,894 from Temple University.…”

An acute immune response underlies the benefit of cardiac adult stem cell therapy

“…In this context the very low retention and rapid clearance of injected adult stem cells may actually be advantageous. These observations may also explain why direct injection into the parenchyma of the heart, as done in the majority of animal studies 7-9 , is universally efficacious while pre-clinical studies using systemic vascular infusion of progenitor cells as performed in the majority of human clinical trials have shown mixed results 4,6,58,59 . Indeed, it is uncertain how systemic vascular delivery of progenitor cells could provide benefit to the heart given the mechanism of action we proposed here, as the vast majority of infused cells do not take up residence in the heart nor persist in the circulatory system 60,61 .Our study was designed to examine the mechanistic basis of adult cardiac stem cell therapy given the new consensus that direct cardiomyocyte regeneration is no longer a tenable mechanism 17,62 and that the adult mammalian heart is largely non-regenerative and does not contain a resident stem cell population [63][64][65] .…”

“…Many independent groups have since repeated these studies with an ever-increasing variety of adult stem cells and while functional improvement is reproducibly observed, nearly all have failed to observe new cardiomyocyte formation from these injected cells [14][15][16][17] . At the same time, clinical trials with adult stem cells in patients with acute myocardial infarction (MI) injury or decompensated heart failure have expanded worldwide over the past 17 years, with thousands of patients enrolled and over $1 billion USD in funding utilized 4,6 . However, while results of these trials have been disappointing, this might simply reflect ineffective trial design because the true mechanistic basis of cell therapy remains unknown 6 .…”

“…At the same time, clinical trials with adult stem cells in patients with acute myocardial infarction (MI) injury or decompensated heart failure have expanded worldwide over the past 17 years, with thousands of patients enrolled and over $1 billion USD in funding utilized 4,6 . However, while results of these trials have been disappointing, this might simply reflect ineffective trial design because the true mechanistic basis of cell therapy remains unknown 6 . For example, more recent literature has shown that the vast majority of transplanted adult stem or progenitor cells simply die within days of delivery into the hearts of ischemia-injured animal models 18,19 , and as such it remains unclear how they might function in a therapeutic manner, although a paracrine hypothesis has been proposed whereby injected cells temporarily release protective growth factors or RNA species [20][21][22] .…”