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Original article
Role and therapeutic potential of vascular stem/progenitor cells in pathological neovascularisation during chronic portal hypertension
  1. Ester Garcia-Pras1,
  2. Javier Gallego1,
  3. Laura Coch1,
  4. Marc Mejias1,
  5. Gonzalo Fernandez-Miranda3,
  6. Ricardo Pardal2,
  7. Jaime Bosch1,
  8. Raul Mendez3,4,
  9. Mercedes Fernandez1
  1. 1 IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
  2. 2 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain
  3. 3 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
  4. 4 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  1. Correspondence to Dr Mercedes Fernandez, IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona 08036, Spain; mercefernandez{at}ub.edu

Abstract

Objective 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.

Design 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.

Results 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.

Conclusions 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.

  • PORTAL HYPERTENSION
  • ANGIOGENESIS

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