Published online before print April 19, 2007

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(American Journal of Pathology. 2007;170:1879-1892.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060646

Human Fetal Aorta Contains Vascular Progenitor Cells Capable of Inducing Vasculogenesis, Angiogenesis, and Myogenesis in Vitro and in a Murine Model of Peripheral Ischemia

Gloria Invernici^*, Costanza Emanueli, Paolo Madeddu, Silvia Cristini^*, Sergio Gadau, Anna Benetti^¶, Emilio Ciusani^||, Giorgio Stassi^**, Mauro Siragusa^**, Roberto Nicosia, Cesare Peschle, Umberto Fascio, Augusto Colombo^¶¶, Tommaso Rizzuti^¶¶, Eugenio Parati^* and Giulio Alessandri^*

From the Neurobiology and Neuroregenerative Therapies Unit^* and Laboratory of Clinical Investigations,|| Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico "C. Besta," Milan, Italy; the Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom; the Department of Molecular and Cellular Medicine and Experimental Medicine and Gene Therapy, National Institute of Biostructures and Biosystems (Inter-Universities Consortium), Osilo and Alghero, Italy; Multimedica IRCCS, Milan, Italy; the Department of Pathology,^¶ University of Brescia, Brescia, Italy; the Department of Surgical and Oncological Science,^** University of Palermo, Palermo, Italy; the Department of Pathology, University of Washington and Veterans Administration Puget Sound Health Care System, Seattle, Washington; the Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Roma, Italy; the Interdepartmental Center of Advanced Microscopy, University of Milan, Milan, Italy; and the Department of Obstetrics and Gynecology,^¶¶ Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy

Vasculogenesis, the formation of blood vessels in embryonic or fetal tissue mediated by immature vascular cells (ie, angioblasts), is poorly understood. We report the identification of a population of vascular progenitor cells (hVPCs) in the human fetal aorta composed of undifferentiated mesenchymal cells that coexpress endothelial and myogenic markers. Under culture conditions that promoted cell differentiation, hVPCs gave rise to a mixed population of mature endothelial and mural cells when progenitor cells were stimulated with vascular endothelial growth factor-A or platelet-derived growth factor-ßß. hVPCs grew as nonadherent cells and, when embedded in a three-dimensional collagen gel, reorganized into cohesive cellular cords that resembled mature vascular structures. hVPC-conditioned medium contained angiogenic substances (vascular endothelial growth factor-A and angiopoietin-2) and strongly stimulated the proliferation of endothelial cells. We also demonstrate the therapeutic efficacy of a small number of hVPCs transplanted into ischemic limb muscle of immunodeficient mice. hVPCs markedly improved neovascularization and inhibited the loss of endogenous endothelial cells and myocytes, thus ameliorating the clinical outcome from ischemia. We conclude that fetal aorta represents an important source for the investigation of the phenotypic and functional features of human vascular progenitor cells.