Cell Therapy for Heart Regeneration: Learning from the Past to Build a Brighter Future

Cell therapy as a means to cure ischemic heart disease and end-stage heart failure has been under investigation for several years. Many clinical studies have been conducted with different cell types: skeletal myoblasts (SM), bone marrow-derived mononuclear cells (BM-MNC), mesenchymal stromal cells (MSC), and resident cardiac stem cells (CSC), to name a few [1, 2]. The efficacy results obtained so far are inconclusive, and cell therapy has never entered into clinical practice. In particular, there are still a few issues hampering an effective translation from the promising preclinical results to the bedside. Among the challenges, the most relevant are the low engraftment rate and the incapacity of the cells to differentiate into fully mature cardiomyocytes, resulting in a lack of heart regeneration which was the original goal that scientists aimed to accomplish when they started testing cell therapy. Despite this apparent unsuccess, much has been learned from the first clinical trials, and these now well-established concepts must drive our choices when designing new cell therapy protocols if we want to eventually succeed in repairing failing hearts. The most recent lesson comes from an observational study, appearing in this issue of STEM CELLS Translational Medicine, in which the (very) long-term fate of SM transplanted into a human heart is described [3]. I like to think about this work as the natural closure of a circle, as the senior author, Philippe Menasché, was the first to transplant SM in a patient back in 2001 [4]. Thanks also to this new study, we now have enough elements to critically retrace the history of SM use for heart disease and to draw final conclusions. The history started in 1996, when Murry and colleagues demonstrated for the first time that neonatal SM could graft into an injured mouse heart and that the engrafted cells initially proliferate and then begin to form multinucleated myotubes that, with time, can differentiate into mature myofibers [5]. They also showed that it was possible to stimulate the contraction of the newly formed muscle ex vivo. However, in vivo, the myotube grafts were isolated from the remaining myocardium and failed to form electrical connections. Based on this positive preclinical evidence (but in hindsight underestimating the negative), Menasché’s group performed the first intramyocardial injection of SM in a human failing heart during an aortic coronary artery bypass graft (CABG) intervention [4]. The reassuring safety data yielded by this pilot study led to the execution of the placebo-controlled, double-blind MAGIC trial [6], in which 97 patients with heart failure were randomly assigned to receive either a low or a high dose of autologous SM or placebo. At 6 months, the high-dose cell group showed a significant decrease in left ventricle volumes compared with the placebo group. However, the study did not achieve its primary endpoint, which was the improvement in left ventricular ejection fraction (LVEF). Moreover, concerns were expressed regarding a potential pro-arrhythmic effect played by SM therapy, likely due to the lack of electrical coupling. Meanwhile, other clinical trials tested the use of SM transplant with results similar to those reported in the MAGIC [7]. For these reasons, the development of therapies based on SM was basically abandoned. Despite this unhappy ending, thanks to the foresight of a few investigators who collected and analyzed the hearts of patients (when they died or received transplant) previously treated with SM, we have learned important concepts from this journey. In 2003, two independent studies described the fate of SM at an intermediate [8] and at a long-time point [9] after intramyocardial transplantation. The first study was a phase I clinical trial investigating the feasibility and safety of autologous SM transplant in patients affected by ischemic heart disease undergoing left ventricular assist device (LVAD) implantation as a bridge to orthotopic heart transplantation. Four hearts were collected at the time of transplant, performed after an average time of 4 months from LVAD implant. Few areas of engrafted SM were identified in trichrome-stained sections and confirmed by immunohistochemistry for the skeletal muscle-specific myosin heavy chain. Additionally, evidence of SM differentiation with expression of slow-twitch myosin isoform was reported. Even though the cells were located in large scarred areas, the majority demonstrated healthy morphology and was mostly aligned in parallel with Coronary Care Unit & Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo Foundation, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; and Department of Medicine, University of Cape Town, Cape Town, South Africa