Ex vivo expanded hematopoietic progenitor cells improve cardiac function after myocardial infarction: Role of β-catenin transduction and cell dose

Background Cell-based therapy after myocardial infarction (MI) is a promising therapeutic option but the relevant cell subsets and dosage requirements are poorly defined. We hypothesized that cell therapy for myocardial infarction is improved by ex vivo expansion and high-dose transplantation of defined hematopoietic progenitor cells (HPCs). Methods and results Since β-catenin promotes self-renewal of stem cells we evaluated the therapeutic efficacy of β-catenin-mediated ex vivo expansion of mouse HPCs in a mouse model of myocardial ischemia/reperfusion followed by intraarterial cell delivery. The impact of cell dose was determined by comparing a low-dose (LD, 5 × 105 cells) vs. a high-dose (HD, 1 × 107 cells) cell transplantation regimen of β-catenin-HPCs. The impact of β-catenin modification of HPCs was determined by comparing control-transduced HPCs (GFP-HPCs) vs. transgenic β-catenin-HPCs. HD β-catenin-HPCs significantly improved LV function and end-systolic and end-diastolic dimensions as compared to saline and LD β-catenin-HPCs. Furthermore, while treatment with HD GFP-HPC resulted in a modest cardiac improvement the application of β-catenin-HPCs was superior, resulting in a significant improvement in EF, FS and LVESD over saline and control GFP-HPC treatment. Although myocardial engraftment of HPCs was only transient, as determined by cell quantification after dye labeling, β-catenin-HPC treatment significantly decreased infarct size, reduced cardiomyocyte apoptosis and increased capillary angiogenesis in vitro and in vivo. Conclusion Ex vivo expanded HPCs improve cardiac function and remodeling post MI in a cell number- and β-catenin-dependent manner.