Current clinical trials of cell-based therapies in cardiac repair: too many variables spoil the stem cell broth

Abstract

This editorial refers to ‘Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis’, by R. Delewi et al. doi:10.1093/eurheartj/eht372 Even the staunchest advocate of the use of cell-based therapies in cardiac repair would be forced to admit that progress has thus far been slow. Both use of therapeutic stem cells and gene-based approaches have met with significant hurdles in their clinical development. However, significant progress does continue to be made towards the ultimate goal of a safe and efficacious cell-based therapy for routine clinical use in cardiac repair. In the area of stem cells, a number of approaches have been proposed, tested pre-clinically, and then clinically evaluated, albeit in relatively small studies thus far.1 These include use of skeletal muscle myoblasts (SKMs), bone marrow-derived mononuclear cells (BMCs), mesenchymal stem cells (MSCs, both bone marrow and adipose tissue derived), and cardiac stem cells. Amongst these, the most rigorously evaluated thus far have undoubtedly been the BMCs. Bone marrow-derived mononuclear cells used therapeutically may be unselected or selected according to characteristic cell surface markers, e.g. CD34+, CD133+, and/or CXCR4+, amongst many other identifiers.2 Putative mechanisms of benefit of BMCs in the post-myocardial infarction (MI) cardiac repair setting have been variously ascribed to both direct transdifferentiation into cardiomyocytes (likely to play only a minimal, if any, role), indirect actions such as vasculogenesis and angiogenesis, antiapoptotic and antinecrotic effects, and favourable paracrine effects on the extracellular matrix.3 Intravascular delivery methods invariably result in only minimal local accumulation and retention of cells within the heart in general and the peri-infarct region specifically post-MI.4 In addition, the cardiac microenvironment in the early post-infarct setting is relatively hostile …