Nicholas Latham

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

Background— Blood-derived circulatory angiogenic cells (CACs) and resident cardiac stem cells (CSCs) have both been shown 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-1&agr; 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 and CSCs provide unique paracrine repertoires with equivalent effects on angiogenesis, stem cell migration, and myocardial repair. Combination therapy with both cell types synergistically improves postinfarct myocardial function greater than either therapy alone. This synergy is likely mediated by the complimentary paracrine signatures that promote revascularization and the growth of new myocardium.

Paracrine Engineering of Human Cardiac Stem Cells With Insulin‐Like Growth Factor 1 Enhances Myocardial Repair

Background Insulin-like growth factor 1 (IGF-1) activates prosurvival pathways and improves postischemic cardiac function, but this key cytokine is not robustly expressed by cultured human cardiac stem cells. We explored the influence of an enhanced IGF-1 paracrine signature on explant-derived cardiac stem cell–mediated cardiac repair. Methods and Results Receptor profiling demonstrated that IGF-1 receptor expression was increased in the infarct border zones of experimentally infarcted mice by 1 week after myocardial infarction. Human explant-derived cells underwent somatic gene transfer to overexpress human IGF-1 or the green fluorescent protein reporter alone. After culture in hypoxic reduced-serum media, overexpression of IGF-1 enhanced proliferation and expression of prosurvival transcripts and prosurvival proteins and decreased expression of apoptotic markers in both explant-derived cells and cocultured neonatal rat ventricular cardiomyocytes. Transplant of explant-derived cells genetically engineered to overexpress IGF-1 into immunodeficient mice 1 week after infarction boosted IGF-1 content within infarcted tissue and long-term engraftment of transplanted cells while reducing apoptosis and long-term myocardial scarring. Conclusions Paracrine engineering of explant-derived cells to overexpress IGF-1 provided a targeted means of improving cardiac stem cell–mediated repair by enhancing the long-term survival of transplanted cells and surrounding myocardium.

Paracrine Engineering of Human Explant‐Derived Cardiac Stem Cells to Over‐Express Stromal‐Cell Derived Factor 1α Enhances Myocardial Repair

First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal‐cell derived factor 1α, which opens the prospect of maximizing up‐front paracrine‐mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal‐cell derived factor 1α. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal‐cell derived factor 1α over‐expression prevented lv‐mediated “loss of cytokines” through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal‐cell derived factor 1α enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal‐cell derived factor 1α enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal‐cell derived factor 1α content paralleled reductions in myocyte apoptosis but did not influence long‐term engraftment or the fate of transplanted cells. Transplantation of stromal‐cell derived factor 1α transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction. Stem Cells 2016;34:1826–1835