Cell Death Discovery (Feb 2024)

Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis

  • Aina Medina-Dols,
  • Guillem Cañellas,
  • Toni Capó,
  • Montse Solé,
  • Marina Mola-Caminal,
  • Natalia Cullell,
  • Marina Jaume,
  • Laura Nadal-Salas,
  • Jaume Llinàs,
  • Lluis Gómez,
  • Silvia Tur,
  • Carmen Jiménez,
  • Rosa M. Díaz,
  • Caty Carrera,
  • Elena Muiño,
  • Cristina Gallego-Fabrega,
  • Carolina Soriano-Tárraga,
  • Laura Ruiz-Guerra,
  • Josep Pol-Fuster,
  • Víctor Asensio,
  • Josep Muncunill,
  • Aarne Fleischer,
  • Amanda Iglesias,
  • Eva Giralt-Steinhauer,
  • Uxue Lazcano,
  • Isabel Fernández-Pérez,
  • Joan Jiménez-Balado,
  • Marina Gabriel-Salazar,
  • Miguel Garcia-Gabilondo,
  • Ting Lei,
  • Nuria-Paz Torres-Aguila,
  • Jara Cárcel-Márquez,
  • Jerònia Lladó,
  • Gabriel Olmos,
  • Anna Rosell,
  • Joan Montaner,
  • Anna M. Planas,
  • Raquel Rabionet,
  • Mar Hernández-Guillamon,
  • Jordi Jiménez-Conde,
  • Israel Fernández-Cadenas,
  • Cristòfol Vives-Bauzá

DOI
https://doi.org/10.1038/s41420-024-01857-z
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 13

Abstract

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Abstract Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient’s blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4–5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.