Vegf‐independent activation of müller cells by the vitreous from proliferative diabetic retinopathy patients

Sara Rezzola, Jessica Guerra, Adwaid Manu Krishna Chandran, Alessandra Loda, Anna Cancarini, Piergiuseppe Sacristani, Francesco Semeraro, Marco Presta

Research output: Contribution to journalArticlepeer-review


Proliferative diabetic retinopathy (PDR), a major complication of diabetes mellitus, results from an inflammation‐sustained interplay among endothelial cells, neurons, and glia. Even though anti‐vascular endothelial growth factor (VEGF) interventions represent the therapeutic option for PDR, they are only partially efficacious. In PDR, Müller cells undergo reactive gliosis, produce inflammatory cytokines/chemokines, and contribute to scar formation and retinal neovascularization. However, the impact of anti‐VEGF interventions on Müller cell activation has not been fully elucidated. Here, we show that treatment of MIO‐M1 Müller cells with vitreous obtained from PDR patients stimulates cell proliferation and motility, and activates various intracellular signaling pathways. This leads to cytokine/chemokine upregulation, a response that was not mimicked by treatment with recombinant VEGF nor inhibited by the anti‐VEGF drug ranibizumab. In contrast, fibroblast growth factor‐2 (FGF2) induced a significant overexpression of various cytokines/chemokines in MIO‐M1 cells. In addition, the FGF receptor tyrosine kinase inhibitor BGJ398, the pan‐FGF trap NSC12, the heparin‐binding protein antagonist N‐tert-butyloxycarbonyl‐Phe‐Leu‐Phe‐Leu‐Phe Boc2, and the anti‐inflammatory hydrocortisone all inhibited Müller cell activation mediated by PDR vitreous. These findings point to a role for various modulators beside VEGF in Müller cell activation and pave the way to the search for novel therapeutic strategies in PDR.

Original languageEnglish (US)
Article number2179
Pages (from-to)1-16
Number of pages16
JournalInternational journal of molecular sciences
Issue number4
StatePublished - Feb 2 2021
Externally publishedYes


  • Diabetic retinopathy
  • Inflammation
  • Müller cells
  • VEGF
  • Vitreous humor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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