Human Blood and Cardiac Stem Cells Synergize to Enhance Cardiac Repair When Cotransplanted Into Ischemic Myocardium

Abstract

Background-Blood-derived circulatory angiogenic cells (CACs) and resident cardiac stem cells (CSCs) have both beenshown to improve cardiac function after myocardial infarction. The superiority of either cell type has long been an area of speculation with no definitive head-to-head trial. In this study, we compared the effect of human CACs and CSCs, alone or in combination, on myocardial function in an immunodeficient mouse model of myocardial infarction. Methods and Results-CACs and CSCs were cultured from left atrial appendages and blood samples obtained from patients undergoing clinically indicated heart surgery. CACs expressed a broader cytokine profile than CSCs, with 3 cytokines in common. Coculture of CACs and CSCs further enhanced the production of stromal cell-derived factor-1α and vascular endothelial growth factor (P≤0.05). Conditioned media promoted equivalent vascular networks and CAC recruitment with superior effects using cocultured conditioned media. Intramyocardial injection of CACs or CSCs alone improved myocardial function and reduced scar burdens when injected 1 week after myocardial infarction (P≤0.05 versus negative controls). Cotransplantation of CACs and CSCs together improved myocardial function and reduced scar burdens to a greater extent than either stem cell therapy alone (P≤0.05 versus CAC or CSC injection alone). Conclusions-CACs

Hyperglycemia Inhibits Cardiac Stem Cell–Mediated Cardiac Repair and Angiogenic Capacity

“…These cells have previously been characterized to represent a heterogeneous population of cardiogenic cells capable of promoting cardiac repair to a degree equivalent to cells under clinical investigation. 19,20 Furthermore, similar heterogeneous CSC products have been reported to be (n=5, right). B, Interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), angiogenin (Ang), angiopoietin (Angpt) 1, and Angpt-2 protein content in conditioned medium prepared from CSCs derived from 5 mmol/L and 25 mmol/L cardiac explant cultures (n=4).…”

“…CSCs were cultured as described previously. 19,20 Hyperglycemia was induced in C57BL/6 or PEP8-hGlo-1 mice by intraperitoneal injection of streptozotocin (50 mg/kg for 5 days) in 0.05 mol/L sodium citrate. Nondiabetic control mice received equal volumes of 0.05 mol/L sodium citrate.…”

Cardiac Stem Cell Treatment in Myocardial Infarction

“…A recent study, which came out later than our systematic search, actually studied the administration of human fetal Sca-1 + cells in a chronic MI model, showing no benefit on functional parameters. 33 Interest and effort has been put into the donor characteristics and cell availability, deeming either autologous or allogeneic cells superior to one another. In our analyses, we could not find a difference between autologous, allogeneic, or even xenogeneic cells, which is also in line with previous findings.…”

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…However, some authors reported signs of stem cell survival up to 1 week [8,16,60,100,104], 1 month [14,18,23,27,30,37,46,52,67,105] and, most strikingly, up to 1 year [26]. When retained cells are quantified, we find that less than 3% of the stem cells survive more than 4 weeks [59,70] and that percentage drops to levels below 1% when the assessment is made 16 weeks after transplantation [106]. The exception is reported by Zhang et al [67] who found that 32% of the implanted iPSC-CMs could survive for 4 weeks in a mice model of AMI.…”