title: Role and therapeutic potential of vascular stem/progenitor cells in pathological neovascularisation during chronic portal hypertension.
abstract: Pathological neovascularisation is intimately involved in portal hypertension (PH). Here, we determined the contribution of vascular stem/progenitor cells (VSPCs) to neovessel growth in PH and whether the RNA-binding protein cytoplasmic polyadenylation element binding protein-4 (CPEB4) was behind the mechanism controlling VSPC function.
  
  
  
  To identify and monitor VSPCs in PH rats (portal vein-ligated), we used a combinatorial approach, including sphere-forming assay, assessment of self-renewal, 5-bromo-2'-desoxyuridine label retention technique, in vitro and in vivo stem/progenitor cell (SPC) differentiation and vasculogenic capability, cell sorting, as well as immunohistochemistry, immunofluorescence and confocal microscopy expression analysis. We also determined the role of CPEB4 on VSPC proliferation using genetically engineered mouse models.
  
  
  
  We demonstrated the existence in the mesenteric vascular bed of VSPCs displaying capability to form cellular spheres in suspension culture, self-renewal ability, expression of molecules commonly found in SPCs, slow-cycling features, in addition to other cardinal properties exhibited by SPCs, like capacity to differentiate into endothelial cells and pericytes with remarkable vasculogenic activity. Such VSPCs showed, after PH induction, an early switch in proliferation, and differentiated in vivo into endothelial cells and pericytes, contributing, structurally and functionally, to abnormal neovessel formation. Quantification of VSPC-dependent neovessel formation in PH further illustrated the key role played by VSPCs. We also demonstrated that CPEB4 regulates the proliferation of the activated VSPC progeny upon PH induction.
  
  
  
  These findings demonstrate that VSPC-derived neovessel growth (ie, vasculogenesis) and angiogenesis cooperatively stimulate mesenteric neovascularisation in PH and identify VSPC and CPEB4 as potential therapeutic targets.
authors.affiliation: IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Garcia-Pras
authors.affiliation: IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gallego
authors.affiliation: IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Coch
authors.affiliation: IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Mejias
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Fernandez-Miranda
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pardal
authors.affiliation: IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Mendez
authors.affiliation: IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernandez
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D006975:Hypertension, Portal / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D013234:Stem Cells / Q000166:cytology*
chemical_list: C554943:CPEB4 protein, rat; D016601:RNA-Binding Proteins
keywords: ANGIOGENESIS; PORTAL HYPERTENSION