Retrograde Cell Therapy

Recently, the delivery of autologous stem cells and progenitor cells into ischemic myocardium emerged as a new treatment option which may augment angiogenesis and improve myocardial repair processes. Experience in patients with acute and subacute myocardial infarction treated with stem cells and endothelial progenitor cells (EPCs) is promising[58-60], although the detectable benefit in terms of myocardial function is not always documented [61, 62]. Although the mechanism of action of recruited bone marrow derived cells is not clearly elucidated in patients, an involvement of angiogenesis and subsequent arteriogenesis is conceivable, in particularly if the delivered cells home in the border zone of an infarcted region. Consistently, human adult EPCs [63] increased capillary density in the periinfarct area of athymic rats, whereas murine lineage-negative mesenchymal stem cells (MSCs) [64] induced collateral growth of an ischemic hindlimb. For the latter effect, hypoxia conditioned medium of the murine MSCs [65] sufficed, containing a rich source of proangiogenic factors such as vascular endothelial growth factor, placenta growth factor, basic fibroblast growth factor and monocyte chemoattractant protein 1. Bone marrow derived mononuclear cells are specifically recruited to the ischemic tissue, upon mobilization from their vascular niches by VEGF or G-CSF implying eNOS-dependent [66] MMP-9 activation and kit-ligand release [67]. Recently, a contribution of Caveolin-1 dependent [68] endocytosis of CXCR4, the EPC-receptor for the mobilizing chemokine SDF-1 (CXCL2), has been identified [69, 70]. Adult endothelial progenitor cells use a variety of well-described adhesion molecules for niche adherence (alpha4 integrin binding to VCAM-1) [70], rolling (L-selectin) [71] and firm attachment to the target area (62-integrins) [72] at the ischemic vasculature.

In own mice experiments, we could demonstrate that embryonic EPCs [73], which are derived at day 7.5 of embryongenesis, home selectively to postischemic myocardium after intravenous application, a process blocked by an unselective selectin antagonist (fucoidin) [74]. In contrast, 62-integrins are not required for recruitment to the heart, since deficiency for ICAM-1 does not alter the number of recruited cells. In larger organisms, the homing of the cells may be improved substantially by regional application by pressure-regulated selective retroinfusion. Preclinical studies in pigs using radiolabeled endothelial progenitor cells revealed an about 6-fold increase of adherent cells using retroinfusion as compared to systemic

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