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Induced pluripotent stem (iPS) cells and endothelial cell generation: SIRT-ainly a good idea!

  • Rute Moura
    Affiliations
    Center for Molecular and Vascular Biology (CMVB), KU Leuven, Belgium
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  • Gian Paolo Fadini
    Affiliations
    Department of Clinical and Experimental Medicine, University of Padova, Medical School, Padova, Italy
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  • Marc Tjwa
    Correspondence
    Corresponding author at: Laboratory of Vascular Hematology (Leibniz Unit), Center for Molecular Medicine, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. Tel.: +49 69 6301 7357; fax: +49 69 6301 7875.
    Affiliations
    Laboratory of Vascular Hematology, Center for Molecular Medicine, Goethe University, Frankfurt, Germany

    Vesalius Research Center (VRC), KU Leuven, VIB, Belgium
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      Regenerative medicine holds great promise to broaden the therapeutic window in various diseases in which surgical and medical treatment options have reached their limits of benefit, including ischemic heart/limb disease and atherosclerosis. Indeed, a new era of medicine would commence if diseased cells could be safely and efficiently replaced by new ones (i.e. cell therapy); for instance, by generating new endothelial cells to build fresh endothelial linings in vivo (vascular regeneration, re-endothelialization of damaged blood vessels) and ex vivo (vessel engineering, re-endothelialization of stents). Embryonic stem cells (ESCs) were readily considered as excellent starting point, given their pluripotency (i.e. the capacity to form every single cell type of the body), stable karyotype, indefinite culturing yet fairly easy handling, and their intrinsic potential to recapitulate embryonic blood vessel development (vasculogenesis) [
      • Thomson J.A.
      • Itskovitz-Eldor J.
      • Shapiro S.S.
      • et al.
      Embryonic stem cell lines derived from human blastocysts.
      ,
      • Levenberg S.
      • Golub J.S.
      • Amit M.
      • Itskovitz-Eldor J.
      • Langer R.
      Endothelial cells derived from human embryonic stem cells.
      ,
      • Yamashita J.
      • Itoh H.
      • Hirashima M.
      • et al.
      Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors.
      ]. When using classical ESC culture conditions (i.e. embryoid body (EB) formation and the use of non-human serum and feeder layers), ESCs were indeed shown to be a proper cell source for endothelial regeneration [
      • Yurugi-Kobayashi T.
      • Itoh H.
      • Yamashita J.
      • et al.
      Effective contribution of transplanted vascular progenitor cells derived from embryonic stem cells to adult neovascularization in proper differentiation stage.
      ,
      • Huang N.F.
      • Niiyama H.
      • Peter C.
      • et al.
      Embryonic stem cell-derived endothelial cells engraft into the ischemic hindlimb and restore perfusion.
      ]. Various groups have subsequently optimized the efficiency to derive functional endothelial cells from ESCs in serum- and EB-free conditions, applicable for clinical scaling [
      • James D.
      • Nam H.S.
      • Seandel M.
      • et al.
      Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent.
      ,
      • Wang Z.Z.
      • Au P.
      • Chen T.
      • et al.
      Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo.
      ]. However, apart from the risk of teratoma formation, the ethical issue of using ESCs in medicine remains a very difficult hurdle to overcome. One potential solution is the use of adult multipotent stem cells with endothelial plasticity, including MAPCs [
      • Aranguren X.L.
      • McCue J.D.
      • Hendrickx B.
      • et al.
      Multipotent adult progenitor cells sustain function of ischemic limbs in mice.
      ], cardiac stem cells [
      • Beltrami A.P.
      • Barlucchi L.
      • Torella D.
      • et al.
      Adult cardiac stem cells are multipotent and support myocardial regeneration.
      ], hematopoietic stem cells [
      • Grant M.B.
      • May W.S.
      • Caballero S.
      • et al.
      Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization.
      ], etc., but their therapeutic efficiency for endothelial regeneration remains unclear and controversial. In addition, more committed adult vascular progenitor cells appear inefficient in regenerating vessels as they predominantly stimulate endogenous repair via paracrine pathways, thereby limited by the compromised conditions of the host (e.g. hypercholesterolemia, diabetes, obesity, ageing, etc.) [
      • Fadini G.P.
      • Tjwa M.
      A role for TGF-beta in transforming endothelial progenitor cells into neointimal smooth muscle cells.
      ].
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