Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types

www.nature.com/npjregenmed REVIEW ARTICLE OPEN Translational cardiac stem cell therapy: advancing from firstgeneration to next-generation cell types Elena Cambria1,2, Francesco S. Pasqualini 1, Petra Wolint1,2, Julia Günter1,2, Julia Steiger1,2, Annina Bopp1,2, Simon P. Hoerstrup1,2,3,4 and Maximilian Y. Emmert1,2,3,4 Acute myocardial infarction and chronic heart failure rank among the major causes of morbidity and mortality worldwide. Except for heart transplantation, current therapy options only treat the symptoms but do not cure the disease. Stem cell-based therapies represent a possible paradigm shift for cardiac repair. However, most of the first-generation approaches displayed heterogeneous clinical outcomes regarding efficacy. Stemming from the desire to closely match the target organ, second-generation cell types were introduced and rapidly moved from bench to bedside. Unfortunately, debates remain around the benefit of stem cell therapy, optimal trial design parameters, and the ideal cell type. Aiming at highlighting controversies, this article provides a critical overview of the translation of first-generation and second-generation cell types. It further emphasizes the importance of understanding the mechanisms of cardiac repair and the lessons learned from first-generation trials, in order to improve cell-based therapies and to potentially finally implement cell-free therapies. npj Regenerative Medicine (2017)2:17 ; doi:10.1038/s41536-017-0024-1 INTRODUCTION Myocardial infarction (MI) mortality decrease1 has contributed with an aging population to the rise of heart failure (HF) incidence.1 After MI, cardiomyocyte death triggers wall thinning, ventricular dilatation, and fibrosis that can cause left ventricular (LV) dysfunction and HF.2 HF counts 30 million patients1 and a ~50% death rate within 5 years post diagnosis.3 Pharmacological therapies and revascularization techniques (e.g., percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)) have improved patient survival and quality of life, but cannot stop or reverse HF. The heart can ultimately be supported by left ventricular assist devices or replaced by transplantation, but organ shortage, high costs, and complex postoperative management limit these strategies. Hence, novel curative treatments are needed. Stem cell therapy has been proposed for heart repair and regeneration. The exact mechanisms of cardiac repair by transplanted cells are merely unknown. Two main hypotheses exist: (1) direct cardiomyogenic/vasculogenic differentiation, and (2) indirect stimulation of the reparative response through paracrine effects.4 Different cell types are under evaluation regarding their regenerative potential. First-generation cell types including skeletal myoblasts (SMs), bone marrow mononuclear cells (BMMNCs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs) were initially introduced. Despite promising preclinical studies, first-generation approaches displayed heterogeneous clinical outcomes.4, 5 Variations between trials may be attributed to differences in design (cell preparation, delivery route, timing, dose, endpoints, and follow-up (FU) methods). Well-conducted recent meta-analyses reviewed the efficacy of (mostly first-generation) cell-based approaches and came to divergent conclusions.6–8 Nevertheless, the field partially switched to second-generation cell types including lineage-guided cardiopoietic cells, cardiac stem/progenitor cells (CSCs/CPCs), and pluripotent stem cells (Fig. 1). This article provides a critical overview of the translation of firstgeneration and second-generation cell types with a particular focus on controversies and debates. It also sheds light on the importance of understanding the mechanisms of cardiac repair and the lessons learned from first-generation trials, in order to improve cell-based therapies and to potentially finally implement cell-free therapies. FIRST-GENERATION CELL TYPES Skeletal myoblasts With the goal of remuscularizing the injured heart and based on the inference that force-generating cells would function in the cardiac milieu and increase cardiac contractility, SMs figured among the first cell types to be tested. They can be obtained in high number from autologous skeletal muscle satellite cells by expansion in vitro, can be activated in response to muscle damage in vivo, and are resistant to ischemia.9 SMs in preclinical trials. Initial studies in small and large animals were encouraging, with SMs participating at heart muscle formation.10, 11 However, SMs were shown to not electrophysiological couple to native cardiomyocytes in rodents.12, 13 Indeed, N-cadherin and connexin-43 expression was downregulated after transplantation.12 SMs did not differentiate into cardiomyocytes in rodents,14 but could surprisingly differentiate into myotubes in 1 Institute for Regenerative Medicine, University of Zurich, Zurich 8044, Switzerland; 2Division of Surgical Research, University Hospital of Zurich, Zurich 8091, Switzerland; 3Heart Center Zurich, University Hospital of Zurich, Zurich, Switzerland and 4Wyss Translational Center Zurich, Zurich, Switzerland Correspondence: Maximilian Y. Emmert () Received: 17 September 2016 Revised: 16 May 2017 Accepted: 22 May 2017 Published in partnership with the Australian Regenerative Medicine Institute Translational cardiac stem cell therapy E Cambria et al. 2 mixed outcomes.31–34 Regarding HSCs, one of the few existing large animal studies found no evidence of myocardial differentiation of CD34+ HSCs, but showed increased angiogenesis/ vasculogenesis, potentially due to paracrine effects on the host vasculature.35 Few large animal and clinical studies were conducted with EPCs and their results were mixed.36–38 Fig. 1 Evolution of translational cardiac regenerative therapies. First-generation cell types such as SMs, BMMNCs, HSCs, EPCs, and MSCs demonstrated feasibility and safety with, however, heterogeneous outcomes and limited efficacy in the clinical setting. In order to better match the target organ, second-generation cell therapies propose the use of cpMSCs, CSCs/CPCs, and CDCs, and pluripotent stem cells such as ESCs and iPSCs. Next-generation therapies for cardiac repair are directed toward cell enhancement (e.g., biomaterials, 3D cell constructs, cytokines, miRNAs) and cellfree concepts (e.g., growth factors, non-coding RNAs, extracellular vesicles, and direct reprograming) sheep,15 although these findings could not be replicated. Small and large animal trials were nonetheless further conducted and displayed an improvement of LV function.15–17 The involved mechanisms were, however, not understood. SMs in clinical trials. Despite the mixed outcomes in preclinical trials, SMs were rapidly translated into the clinics with phase-I trials in both MI and HF.18–23 Although the transplantation of autologous SMs displayed an arrhythmogenic potential in a ph (...truncated)