title: Neuroblast survival depends on mature vascular network formation after mouse stroke: role of endothelial and smooth muscle progenitor cell co-administration.
abstract: Pro-angiogenic cell-based therapies constitute an interesting and attractive approach to enhancing post-stroke neurogenesis and decreasing neurological deficit. However, most new stroke-induced neurons die during the first few weeks after ischemia, thus impairing total recovery. Although the neovascularization process involves different cell types and various growth factors, most cell therapy protocols are based on the biological effects of single-cell-type populations or on the administration of heterogeneous populations of progenitors, namely human cord blood-derived CD34(+)  cells, with scarce vascular progenitor cells. Tight cooperation between endothelial cells and smooth muscle cells/pericytes is critical for the development of functional neovessels. We hypothesized that neuroblast survival in stroke brain depends on mature vascular network formation. In this study, we injected a combination of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), isolated from human umbilical cord blood, into a murine model of permanent focal ischemia induced by middle cerebral artery occlusion. The co-administration of SMPCs and EPCs induced enhanced angiogenesis and vascular remodeling in the peri-infarct and infarct areas, where vessels exhibited a more mature phenotype. This activation of vessel growth resulted in the maintenance of neurogenesis and neuroblast migration to the peri-ischemic cortex. Our data suggest that a mature vascular network is essential for neuroblast survival after cerebral ischemia, and that co-administration of EPCs and SMPCs may constitute a novel therapeutic strategy for improving the treatment of stroke.
authors.affiliation: INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de Chapelle, 75475 Paris Cedex 10, France.
authors.forename: Lina R
authors.initials: LR
authors.lastname: Nih
authors.forename: Nicolas
authors.initials: N
authors.lastname: Deroide
authors.forename: Carole
authors.initials: C
authors.lastname: Leré-Déan
authors.forename: Dominique
authors.initials: D
authors.lastname: Lerouet
authors.forename: Mathieu
authors.initials: M
authors.lastname: Soustrat
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Levy
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Tatiana
authors.initials: T
authors.lastname: Merkulova-Rainon
authors.forename: Marc
authors.initials: M
authors.lastname: Pocard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kubis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D043169:Endostatins / Q000494:pharmacology; D042783:Endothelial Cells / Q000502:physiology / Q000637:transplantation*; D005312:Fetal Blood / Q000166:cytology; D051157:Frizzled Receptors / Q000378:metabolism; D007839:Functional Laterality; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000502:physiology / Q000637:transplantation*; D009389:Neovascularization, Pathologic / Q000209:etiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D020533:Angiogenesis Inhibitors; D002135:Calcium-Binding Proteins; D043169:Endostatins; C549560:FZD9 protein, human; D051157:Frizzled Receptors; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C562050:P17 peptide; D010455:Peptides; D001973:Bromodeoxyuridine