Cardiac stem cells in the post-Anversa era | European …

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At the turn of the century, prevailing dogma stated that the adult mammalian heart was incapable of self-repair. Postnatal growth reflected increases in cardiomyocyte size alone rather than through increases in cell number. This dogma was shaken by the demonstration that bone marrow cells could be used to regenerate heart muscle. The subsequent discovery that adult hearts contained cells that expressed the haematological stem cell marker c-Kit led to a large body of literature, mostly from Piero Aversas laboratory, which advanced the premise that cardiac c-Kit+ cells were clonogenic, multipotent, and capable of self-renewal (i.e. genuine heart stem cells). While this hypothesis was popularized and espoused by many, the validity of Anversas findings were questioned early on by several investigators who failed to reproduce key findings.1,2

On 14 October 2018, the Harvard Medical School and Brigham and Womens Hospital brought an end to this chapter as 31 papers from the lab pioneering heart c-Kit+ cells were recommended for retraction because the validity of the scientific data was uncertain. While the full identity of the papers affected is still unknown, the New England Journal of Medicine promptly issued an expression of concern that the data presented in two (heretofore) landmark papers in cardiac regeneration may not be reliable3 and outright retracted a 2011 paper demonstrating evidence for human lung c-Kit+ stem cells.4

On the heels of multiple corrections,511 institutional settlements,12 lawsuits,13 and prior retractions,14 it appears much of the literature supporting resident (in situ) c-Kit+ cells having any role in cardiac repair is open to question. The impact of this verdict is only now starting to be understood and has led many to question the concept of heart stem cells in the post-Anversa era.

Yes. Archaeological carbon-14 dating conclusively established that half of all cardiomyocytes are renewed over an individual lifespan.15 This repopulation decreases with advanced years. For example, at 25years old almost 1% of cardiomyocytes turn-over every year compared with only 0.5% turnover after 75years. Such numberslow but definitely not zerohave been confirmed by others using complementary methods in experimental animals.16,17

No. Reports began to emerge 10years ago questioning the cardiomyogenic potential of c-Kit+ cells.1820 Recent lineage tracking from multiple labs using complimentary techniques has established that endogenous cardiac c-Kit+ cells do not generate cardiomyocytes.2123

Probably not. Early reports panned through tissue lysate and heart sections for cells expressing embryonic or haematological stem markers in hopes of identifying cells that could be enticed to express cardiac markers in culture. In the absence of lineage tracking, the origin of the cells discovered is uncertain and very well may represent extra-cardiac contamination. It follows that cardio myogenesis seen before or after injury likely arises from myocardial de-differentiation only.24 Although cardiosphere-derived cells (CDCs) are clonogenic and multipotent in vitro,25 they have long been recognized not to function as cardiac progenitors after transplantation in vivo.26

In 2004, Messina et al. demonstrated a mixed population of CD105+ CD45-cells, explant-derived cells that spontaneously emigrate from heart tissue plated in culture.27 Forensic analysis showed these cells are intrinsically cardiac with no detectable seeding from extra-cardiac organs.28 To enable cell expansion to clinical doses, explant-derived cells have been antigenically selected or sphere cultured to generate c-Kit+ cells or CDCs, respectively (see Figure1). Independent labs have shown that both c-Kit+ cells (6 labs) or CDCs (45+ labs) improve heart function when delivered after injury. Unfortunately, studies providing direct comparisons between either cell type are often difficult to interpret as divergent cell culture methods or patient comorbidities influence cell potency; however, within CDCs, the small c-Kit+ cell fraction does not contribute to and is not necessary for, the observed gains in function.29

Figure 1

Schematic outline of heart-derived cell therapeutic manufacturing and identity. Explant-derived cells are cultured from myocardial tissue for antigenic selection (c-Kit+ cells, left panels) or sphere culture (CDCs, right panels) prior to expansion. Representative c-Kit+ cell images demonstrate freshly isolated human c-Kit+ cells (left panel, black dots, beads from magnetic-activated cell sorting) and during cell expansion (right panel, low confluence to highlight cell morphology). Representative images of CDCs cultured from transgenic mouse tissue expressing the c-Kit reporter (green fluorescent protein)18 highlighting the proportion of c-Kit+ cells within. Also shown is flow cytometry characterization from the SCIPIO (c-Kit+ cell trial, left panel)35 and CADUCEUS (CDC trial, right panel)41 trials contrasting the antigenic identity of each heart-derived cell therapeutic used in clinical trials.

Figure 1

Schematic outline of heart-derived cell therapeutic manufacturing and identity. Explant-derived cells are cultured from myocardial tissue for antigenic selection (c-Kit+ cells, left panels) or sphere culture (CDCs, right panels) prior to expansion. Representative c-Kit+ cell images demonstrate freshly isolated human c-Kit+ cells (left panel, black dots, beads from magnetic-activated cell sorting) and during cell expansion (right panel, low confluence to highlight cell morphology). Representative images of CDCs cultured from transgenic mouse tissue expressing the c-Kit reporter (green fluorescent protein)18 highlighting the proportion of c-Kit+ cells within. Also shown is flow cytometry characterization from the SCIPIO (c-Kit+ cell trial, left panel)35 and CADUCEUS (CDC trial, right panel)41 trials contrasting the antigenic identity of each heart-derived cell therapeutic used in clinical trials.

Not as much as we thought! Ex vivo expanded c-Kit+ cells were inspired by the Anversa literature and it was thought, until recently, that robust cell numbers persisted for many years after intramyocardial injection.30 The in situ c-Kit+ cell findings, which largely emanated from the well-funded Anversa lab, were directly extended to ex vivo expanded c-Kit+ cells. Since then, it has been concretely established that few transplanted cells engraft beyond a few days.31 This surprising observation revealed that c-Kit+ cells were evanescent, and thus not functioning as stem cells.

This realization came very late for c-Kit+ cells, unlike CDCs, which have been known for >10years to be effective despite little persistence of injected cells beyond 4weeks (i.e. 23% of the initial injectate).32,33 Fortunately, the CDC literature provides a clear template for these investigations with several articles listing comprehensive proteomic analysis, cytokine over-expression/subtraction data supporting causation, exosome profiling data and microRNA addition/subtraction data supporting a causative role in post infarct repair.34

Although very late in the game, a great deal of the basic phenotyping work is not yet known about c-Kit+ cells; including the fundamental differences between heart-derived and extra-cardiac c-Kit+ cells. It may be that c-Kit+ cells stimulate many of the immunomodulatory (macrophage polarization) and trophic (angiogenic, anti-apoptotic, mitotic and anti-scarring) endogenous repair mechanisms already identified in the CDC literature but much waits to be uncovered.

Reports of their death have been greatly exaggerated. The 2011 Phase 1 SCIPIO Trial demonstrated intra-coronary injection of c-Kit+ cells was safe and provided encouraging hints of efficacy as shown by increases in cardiac ejection fraction, New York Heart Association (NYHA) class and viable myocardium.35 But the subsequent 2014 expression of concern by The Lancet36 reflected cell product characterization, identity and manufacturing which were both done in Boston by Dr Anversas team.37 The impact of recent events on interpretation of the SCIPIO Trial is still not known but may emerge as the journals affected by the list of articles recommended for retraction receive more information.

The CONCERT HF Trial (ClinicalTrials.gov Identifier: NCT02501811) began in 2015 to explore the effects of combining heart-derived c-Kit+ cells with blood mesenchymal stem cells on post infarct repair.38 This trial was based upon two preclinical studies suggesting combined therapy increases transplanted cell engraftment to enhance cell treatment outcomes.39,40 With the Harvard c-Kit+ cell retractions, the NIHBLI paused the trial on 29 October 2018 to provide the Data and Safety Monitoring Board (DSMB) an opportunity to review the literature supporting the scientific foundations of the trial. Given the invasive nature of the trial (and the observation that a patient died during endomyocardial biopsy), this caution is appreciated to ensure that sufficient pre-clinical insight and clinical equipoise still exist in the new post-Anversa era.

At best, the future of heart c-Kit+ cells is uncertain. With the astounding number of key publications likely to be retracted, it may very well be that adult c-Kit+ cells are not fundamentally different enough from other heart-derived cells to warrant efforts exploring clinical efficacy beyond the multiple clinical trials completed or underway using CDCs or the CDC secretome.

Conflict of interest: none declared.

References are available as supplementary material at European Heart Journal online.

Published by Oxford University Press on behalf of the European Society of Cardiology 2019.

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Cardiac stem cells in the post-Anversa era | European ...

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