Cell-based cardiac regeneration

Abstract

further work to develop novel technologies in resistant disease is pursued. In the end, the regenerative medicine model of care moves the current pattern of practice away from one that fights against disease towards one that perpetuates healing from within, to protect against chronic disease. Bioeconomy Regenerative biotechnology offers the prospect of unprecedented solutions for many global health challenges. Adoption of a growing regenerative armamentarium into mainstream practice is projected to fuel 10% of the overall economic healthcare output within a decade. This emerging 'bioeconomy', fostered by public/private initiatives , is evolving to expedite timely and regimented incorporation of new biotherapies into the core healthcare portfolio. To address the needs of a rapidly aging and vulnerable population, the aspirational goal is to match increasing lifespan with healthspan in a cost-effective manner. Within a 2030 horizon, affordable access to proven regenerative therapies will be paramount in ensuring equitable coverage for at-risk populations. A unique opportunity in this space is the prospect of off-the-shelf and point-of-care technologies. These platforms provide the ability for two-to-three orders of magnitude scale-up in biomanu-facturing to mitigate variability in function and assure quality. This is in contrast to the current state-of-the-art, where often single cell doses are manufactured and released at high cost. The burden of cost-intense cell manufacturing can be mitigated if the knowhow and biology carried forward from the stem cell era is translated into acellular alternatives aiming to provide consistent therapeutic performance, at low cost, for treated populations. Thus, clinical grade regenerative biotechnology must remain open to ongoing adaptation and continuous improvement in order to overcome technological limitations identified in early prototypes. In this context, aligning incentives for developing health therapies, including early reimbursement, with public health goals can serve as a catalyst to expedite transition into a regenerative model of care without disrupting current healthcare systems. The multidimensional fabric of regenerative medicine is intrinsic to the success of this emerging discipline. A unified public/private endeavour , that encompasses a holistic view of regenerative science, while accounting for population/patient diversity and practicality of practice application, will augment ultimate success. Thus, the path to making regeneration great again will be realized through a shared vision of strength together. Cell-based cardiac regeneration Current evidence, clinical controversies, translational hurdles, and future challenges for therapies. 'The Holy Grail' is still pending! Cardiac cell therapy has been repeatedly suggested as a promising therapeutic approach for the repair and regeneration of the diseased heart. 1-3 While numerous encouraging preclinical data 4-6 have facilitated fast clinical translation, 7-10 the currently available human data display only heterogeneous or limited therapeutic efficacy. 1,9,10 The reasons for this lack of translation are multi-faceted and many key questions regarding the optimal strategy (i.e. the ideal cell-type, timing and dosing of therapy or patient selection) remain to be elucidated. Of note, most of the initial human trials have primarily utilized un-selected, first generation cell types, bone marrow derived mononu-clear cells, which have been shown to come with a limited cardio-reparative capacity (Figure 1). 11 Additionally, from a methodological standpoint, in the currently available cell therapy trials major inconsistencies and controversies exist in regard to study-design, sample-size, and endpoints which makes their direct comparison and interpretation almost impossible. 12 These controversies were recently highlighted in various well-conducted meta-analyses that reviewed the potential efficacy of cell therapy (mostly first-generation cell-types) to treat acute myocardial infarction (MI) and chronic heart-failure (HF). 10,13,14 As one of the currently most interesting analyses in the setting of acute MI, the ACCRUE meta-analysis (analysis of cell-based cardiac studies; NCT01098591) has analysed 1252 individual patient data-sets (IPD) from 12 randomized trials of intracoronary cell therapy and detected no therapeutic advantage of cell therapy when compared to controls. 10 In line with that, and interestingly, Jong et al. highlighted that no effect was detectable after cell therapy when cardiac magnetic