Clinical trials of bone marrow derived cells for ischemic heart failure. Time to move on? TIME, SWISS-AMI, CELLWAVE, POSEIDON and C-CURE

The two adult types of bone marrow (BM) can be distinguished: the red marrow consisting of hematopoietic tissue, including Hematopoietic Stem Cells (HSCs) capable of producing around 500 billion blood cells per day; and the yellow marrow mainly made up of fat cells. BM contains two types of stem cells: hemopoietic (which can produce blood cells) and stromal (which can produce fat, cartilage and bone). Mesenchymal Stem Cells (MSCs), first described in 1970 in BM,1 emerged as an extremely promising therapeutic cell based agent for tissue regeneration and were broadly characterized in that sense.2,3In vitro studies demonstrated that MSCs present attractive characteristics like immune-regulatory effects; capacity to stimulate neovascularization, endogenous stem cell proliferation and differentiation, capacity to modify the micro-environment, prevent scarification, fibrosis and aptitude to differentiate into various mesoderm derived tissue. Notably, myocytes and cardiomyocyte differentiation ability was shown in multiple studies.4–9 All together these properties drove enthusiasm for MSCs and particularly BM derived MSCs (BM-MSCs) use in cardiac regeneration. MSCs represent 0.001 to 0.01% of BM nucleated cells and, it is now broadly accepted that MSCs cultures represent a mix of various cells with various degrees of “stemness”.10,11 The unforeseen discovery that HSCs isolated from BM present the ability to repair infarcted myocardium12 also prompted extensive research in this direction. Though, HSCs only represent ∼0.01% of BM mononucleated cells, and there expansion in vitro remains elusive,13 therefore, clinical trials to date relied on whole BM use, impairing the clear identification of which cellular actor drives the observe effect. Therefore, very short time after the publication of the first experimental study of the use of Bone Marrow Cells (BMCs) for the treatment of post Myocardial Infarction (MI) heart failure (HF) in a small animal model,14 clinical trials of this form of therapy started.15 This was followed by an extremely large number of trials with mixed results,16–20 and even the alarming establishment of commercial clinics in different countries. All together, these findings lead in the last year to witness the publication of several trials in the field using either whole BMCs or BM-MSCs. The results of the most recently publish results are reviewed here with the hope of clarifying some of the major issues in the field. In addition, an article expressing concerns regarding some of the early trials is described.