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Objectives: Cell therapy may offer novel therapeutic options for chronic ischemic heart disease. In a clinical trial, we first assessed the feasibility and safety of intramyocardial CD133+ bone marrow cell injection together with coronary artery bypass grafting (CABG). We then tested the hypothesis that CABG plus CD133+ cell injection would result in better contractile function than CABG alone. Methods: Fifteen patients took part in the safety study, followed by 40 patients who underwent either CABG with cell therapy or CABG alone. Bone marrow was harvested from the iliac crest one day before surgery, and purified CD133+ progenitor cells were injected in the infarct border zone during the CABG operation. LV function was measured by echocardiography and myocardial perfusion by SPECT. Results: In the safety study, no procedure-related complications were observed for up to 3 years. LV injection fraction (LVEF) increased from 39.0% ± 8.7% preoperatively to 50.2% ± 8.5% at 6 months and 47.9% ± 6.0% at 18 months (F = 6.03, P = .012). In the efficacy study, LCEF rose form 37.4% ± 8.4% to 47.1% ± 8.3% at 6 months in the group with CABG and cell therapy (F = 24.16, P < .0001) but only from 37.9% ± 10.3% to 41.3% ± 9.1% in the CABG-only group (F = 7.72, P = .012). LVEF was significantly higher at 6 months in the group with CABG and cell therapy than in the CABG-only group (P = .03). Similarly, perfusion of the infarcted myocardium improved more in patients treated with CABG and cell therapy than in those treated with CABG alone. Conclusion: Intramyocardial delivery of purified bone marrow stem cells together with CABG surgery is safe and provides beneficial effects, though it remains to be seen whether thewe effects produce a lasting clinical advantage. [Copyright &y& Elsevier]

Abstract: Objective: We tested the hypothesis that intravenously administered human umbilical cord blood (hUCB) cells contribute to repair processes following myocardial infarction. Methods: hUCB mononuclear cells containing 0.11% to 1.1% CD34+ cells were injected in the tail vein of NOD/scid mice that had (MI+) or had not (MI−) previously undergone ligation of the left anterior coronary artery (LAD). Homing to bone marrow and solid organs was determined by polymerase chain reaction (PCR) for human DNA (hDNA) using human-specific primers of Locus D7Z1. Immunostaining was used for phenotypic analysis, and capillary density as well as myocardial scar formation was assessed. Moreover, expression of stromal cell-derived factor-1 (SDF-1) was studied in infarcted and in normal hearts. Results: hDNA was detected in marrow, spleen, and liver of both MI+ and MI− mice 24 h, 1 week, and 3 weeks after cell injection. In the heart, however, hDNA was detected in 10 of 19 MI+ mice but in none of the MI− mice (p=0.002). Infarct size was smaller in cell-treated MI+ mice than in untreated MI+ hearts (38.7 versus 47.8%, P&#60;0.05), and there was also less collagen deposition. In cell-treated MI+ mice, capillary density in the infarct border zone was approximately 20% higher (p=0.03), and clusters of hUCB-derived cells were detected in the perivascular interstitium. Occasionally, chimeric capillaries composed of human and mouse endothelial cells were found, but the vast majority of neo-vessels appeared to consist of mouse cells only. Up to 70% of the cord blood-derived cells in the heart were CD45+. There was no evidence of cardiomyocyte differentiation as determined by co-localization of HNA or HLA-I with GATA-4 or Connexin 43. In infarcted myocardium, expression of SDF-1 mRNA was approximately 7-fold higher than in normal hearts. Conclusions: hUCB cells migrate to infarcted, not to normal myocardium, where they engraft, participate in neoangiogenesis, and beneficially influence remodelling processes. Cord blood cells may hence be useful for cell therapy of ischemic heart disease. [Copyright &y& Elsevier]

The molecular mechanisms of interferon-alpha (IFN-α)-mediated cell growth inhibition are incompletely understood. Here, we have analysed how IFN-α interferes with the interleukin-3 (IL-3)-stimulated cell cycle progression by Ba/F3 cells. The antiproliferative cytokine caused a delay in cell cycle progression, which correlated with a diminished activation of the cyclin-dependent kinases 2 and 4 in IL-3-stimulated cells. While IFN-α did not affect the expression of p27Kip1 and p21Waf1, it efficiently inhibited the IL-3-induced expression of D-type cyclin and cyclin E proteins. No IL-3-antagonistic effects of the IFN, however, were observed at the mRNA level of cyclin expression. Furthermore, IFN-α suppressed the IL-3-induced release of E2F transcription factors from the retinoblastoma protein (pRb) and enhanced pRb-mediated transcriptional repression. The growth factor-antagonistic action of IFN-α correlated with a strong stimulation of protein kinase R expression, suggesting that inhibition of protein synthesis plays a pivotal role in IFN-α-mediated inhibition of cell cycle progression. [Copyright &y& Elsevier]