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(Circulation Research. 2009;104:1095.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Human CD133⁺ Progenitor Cells Promote the Healing of Diabetic Ischemic Ulcers by Paracrine Stimulation of Angiogenesis and Activation of Wnt Signaling

Lucíola S. Barcelos^*, Cécile Duplaa^*, Nicolle Kränkel^*, Gallia Graiani^*, Gloria Invernici, Rajesh Katare, Mauro Siragusa, Marco Meloni, Ilaria Campesi, Manuela Monica, Andreas Simm, Paola Campagnolo, Giuseppe Mangialardi, Lara Stevanato, Giulio Alessandri, Costanza Emanueli, Paolo Madeddu

From the Bristol Heart Institute (L.S.B., N.K., R.K., M.S., M. Meloni, P.C., G.M., C.E., P.M.), Department of Clinical Science at South Bristol, University of Bristol, United Kingdom; Institut National de la Santé et de la Recherche Médicale U828 (C.D.), University Victor Segalen-Bordeaux II, France; Department of Pathology (G.G., M. Monica), University of Parma, Italy; Neurobiology and Neuroregenerative Therapies Unit (G.I., G.A.), Carlo Besta Neurological Institute, Milan, Italy; Experimental Medicine and Gene Therapy Section (I.C.), National Institute of Biostructures and Biosystems (INBB), Osilo (Sassari), Italy; Department of Cardio-Thoracic Surgery (A.S.), Martin-Luther University of Halle-Wittenberg, Halle, Germany; and Department Stem Cell Discovery (L.S.), ReNeuron Ltd, Guildford, United Kingdom.

Correspondence to Paolo Madeddu, MD, CS, FAHA, Bristol Heart Institute, University of Bristol, Upper Maudlin St, Bristol, BS2 8HW, United Kingdom. E-mail madeddu{at}yahoo.com

We evaluated the healing potential of human fetal aorta-derived CD133⁺ progenitor cells and their conditioned medium (CD133⁺ 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 2x10⁴ CD133⁺ or CD133^– cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133⁺ cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133^– cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133⁺ cells accelerated wound closure as compared with CD133^– or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133⁺ cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133⁺ 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⁺ CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133⁺ CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133⁺ 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.

Key Words: ischemia • wound healing • diabetes • stem cells • angiogenesis

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Chu-Huang Chen, Richard A.F. Dixon, Liang-Yin Ke, and James T. Willerson
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