Abstract 299: Transplantation of Hypoxia-preconditioned Cardiac Stem Cells Improves Infarcted Heart Function Via Cxcr4 Upregulation and Improved Survival of Implanted Cells
The chemokine stromal-derived factor-1α (SDF-1α) and its receptor CXCR4 are implicated as key mediators of in homing and trafficking bone marrow derived stem cells (BMSC) toward ischemic myocardium after acute myocardial infarction (MI), however, the CXCR4 expression in cardiac stem cells (CSCs) is very low compared to BMSC. Upregulation of CXCR4 expression in CSCs may facilitate implanted CSC homing to ischemic myocardium, and enhance hear regeneration after intravenous transplantation. Mouse c-kit+ cardiac stem cells were cultured under normoxic or hypoxic conditions. Expression of CXCR4 and anti-apoptotic genes was examined by immunoblot. In vivo, we induced myocardial infarction by LAD ligation, and then intravenously injected hypoxia preconditioned (PC) CSCs, non-PC CSCs, AMD3100 treated PC-CSCs and media at 1hrs after MI. Heart function was measured at 1w, 2w and 4w post-MI using Vevo 770, a high-resolution (30 MHz) ultrasound system. In isolated CSCs, CXCR4 were upregulated by hypoxia treatment, which resulted in increased phosphorylation of both AKT and Src activation by SDF-1α and decreased phosphorylation of Caspase 3. Cultured CSC pretreated with hypoxia were resistant to H2O2 damage, exhibiting less trypan blue uptake, and apoptotic cell death using TUNEL assay (P<0.05). This protective effect was blocked by the lentivirus mediated CXCR4 siRNA. Our data demonstrated that PC-CSCs increase left ventricular ejection fraction (EF) compared to non-PC CSC group (64.9%±3.9% vs. 43.0%±2.9%; P<0.05; n=10), however, the improvement in EF with PC-CSCs was blocked by AMD3100. We conclude that CXCR4 is unregulated in CSCs in response to hypoxic preconditioning, which activate the antiapoptotic AKT pathway and promoting infused cell recruitment into acute ischemic myocardium that has high level of SDF-1 α expression, and facilitate myocardial regeneration against ischemic damage.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).