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Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7·2 [SD 3·4] vs 33·2 [6·0] cells/mm 2, n=4 per group, p<0·02) resulting in greater left-ventricular mass (1·24 [0·29] vs 1·57 [0·27] g) and better cardiac function (shortening fraction 9·2 [4·9] vs 17·2 [4·2]%, n=8 per group, p<0·05). These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is reestablished.

Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF‐1:CXCR4 expression is compromised in post‐AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell‐derived factor‐1 (SDF‐1). SDF‐1 expression in control MSC and SDF‐1‐overexpressing MSC (SDF‐1:MSC) were quantified using enzyme‐linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF‐1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF‐1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF‐1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post‐AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post‐AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF‐1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF‐1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over‐express of SDF‐1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF‐1 may improve post‐AMI cardiac repair in diabetes. Stem Cells Translational Medicine 2018;7:115–124 The SDF‐1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of acute myocardial infarction (AMI). Over‐express of stromal cell‐derived factor‐1 (SDF‐1) expression in diabetes rescues cardiac function post AMI. Results suggest that modulation of SDF‐1 may improve post‐AMI cardiac repair in diabetes.

In this study the effect of local adenoviral-mediated delivery of inducible nitric oxide synthase on restenosis was evaluated in a porcine coronary stented model. Local gene transfer of recombinant adenoviral vectors that encode human inducible nitric oxide synthase (AdiNOS) was tested. Control vector (AdNull) lacked a recombinant transgene. Endoluminal delivery of 1.0 × 1011 adenoviral particles was accomplished in 45 s using the Infiltrator catheter (Interventional Technologies, San Diego, CA). Coronary stents were deployed, oversized by a ratio of 1.2:1, in the treated segments immediately after gene transfer. Fourteen animals were sacrificed at day 28 to evaluate the effects of iNOS gene transfer on morphometric indices, and 4 animals were sacrificed at day 4 for detection of human iNOS expression by RT-PCR. iNOS mRNA was detected in six of eight iNOS-transferred arteries, whereas no expression of human iNOS was detected in the nontarget arteries. Morphometric analysis showed that iNOS transfer significantly reduced neointimal formation (3.41 ± 1.12 mm2 vs 2.14 ± 0.68 mm2, P < 0.05). We concluded that efficient intramural adenovirus-mediated iNOS transfer can be achieved by using Infiltrator catheters. iNOS gene transfer significantly reduces neointimal hyperplasia following stent injury.