Neuroblast survival depends on mature vascular network formation after mouse stroke: role of endothelial and smooth muscle progenitor cell co-administration

Authors

  • Lina R. Nih,

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
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  • Nicolas Deroide,

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
    2. University Paris Diderot, Sorbonne Paris Cité, Paris, France
    3. AP-HP, Hôpital Lariboisière, Service de Physiologie, Université Paris 7, France
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  • Carole Leré-Déan,

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
    2. IVS, Hôpital Lariboisière, Paris, France
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  • Dominique Lerouet,

    1. EA 4475, Equipe de recherche ‘Pharmacologie de la Circulation Cérébrale’, Université Paris Descartes, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • Mathieu Soustrat,

    1. EA 4475, Equipe de recherche ‘Pharmacologie de la Circulation Cérébrale’, Université Paris Descartes, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • Bernard I. Levy,

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
    2. University Paris Diderot, Sorbonne Paris Cité, Paris, France
    3. AP-HP, Hôpital Lariboisière, Service de Physiologie, Université Paris 7, France
    4. IVS, Hôpital Lariboisière, Paris, France
    5. INSERM U970, Cardiovascular Research Center, Paris, France
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  • Jean-Sébastien Silvestre,

    1. INSERM U970, Cardiovascular Research Center, Paris, France
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  • Tatiana Merkulova-Rainon,

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
    2. IVS, Hôpital Lariboisière, Paris, France
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  • Marc Pocard,

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
    2. University Paris Diderot, Sorbonne Paris Cité, Paris, France
    3. AP-HP, Hôpital Lariboisière, Service de Physiologie, Université Paris 7, France
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  • Isabelle Margaill,

    1. EA 4475, Equipe de recherche ‘Pharmacologie de la Circulation Cérébrale’, Université Paris Descartes, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • Nathalie Kubis

    1. INSERM U965, Angiogenesis and Translational Research Center, Hôpital Lariboisière, 41 Bld de la Chapelle, 75475 Paris Cedex 10, France
    2. University Paris Diderot, Sorbonne Paris Cité, Paris, France
    3. AP-HP, Hôpital Lariboisière, Service de Physiologie, Université Paris 7, France
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Nathalie Kubis, 1INSERM U965, as above.
E-mail: nathalie.kubis@lrb.aphp.fr

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.

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