Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling

Barcelos, L. S. et al. (2009) Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling. Circulation Research, 104(9), pp. 1095-1102. (doi: 10.1161/CIRCRESAHA.108.192138)

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Publisher's URL: http://dx.doi.org/10.1161/CIRCRESAHA.108.192138

Abstract

We evaluated the healing potential of human fetal aorta-derived CD133<sup>+</sup>progenitor cells and their conditioned medium (CD133<sup>+</sup> CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2×10<sup>4</sup> CD133<sup>+</sup> or CD133<sup>−</sup> cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133<sup>+</sup> cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133<sup>−</sup> cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133<sup>+</sup> cells accelerated wound closure as compared with CD133<sup>−</sup> or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133<sup>+</sup> cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133<sup>+</sup> CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by coadministering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133<sup>+</sup> CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133<sup>+</sup> CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133<sup>+</sup> cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Meloni, Dr Marco
Authors: Barcelos, L. S., Duplaa, C., Krankel, N., Graiani, G., Invernici, G., Katare, R., Siragusa, M., Meloni, M., Campesi, I., Monica, M., Simm, A., Campagnolo, P., Mangialardi, G., Stevanato, L., Alessandri, G., Emanueli, C., and Madeddu, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN:0009-7330
ISSN (Online):1524-4571

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