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
Affiliations
- Aina Medina-Dols
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Guillem Cañellas
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Toni Capó
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Montse Solé
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Marina Mola-Caminal
- Neurology, Hospital del Mar Medical Research Institute
- Natalia Cullell
- Neurology, Hospital Universitari Mútua de Terrassa/Fundacio Docència i Recerca Mútua Terrassa
- Marina Jaume
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Laura Nadal-Salas
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Jaume Llinàs
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Lluis Gómez
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Silvia Tur
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Carmen Jiménez
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Rosa M. Díaz
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Caty Carrera
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Elena Muiño
- Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU)
- Cristina Gallego-Fabrega
- Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU)
- Carolina Soriano-Tárraga
- Neurology, Hospital del Mar Medical Research Institute
- Laura Ruiz-Guerra
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Josep Pol-Fuster
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Víctor Asensio
- Department of Genetics (GEN-IB), HUSE, IdISBa
- Josep Muncunill
- Genomic & Bioinformatics Platform, IdISBa
- Aarne Fleischer
- Genomic & Bioinformatics Platform, IdISBa
- Amanda Iglesias
- Department of Respiratory Medicine,, Hospital Universitari Son Espases-IdISBa Palma, Spain; CIBERES, Instituto de Salud Carlos III
- Eva Giralt-Steinhauer
- Neurology, Hospital del Mar Medical Research Institute
- Uxue Lazcano
- Neurology, Hospital del Mar Medical Research Institute
- Isabel Fernández-Pérez
- Neurology, Hospital del Mar Medical Research Institute
- Joan Jiménez-Balado
- Neurology, Hospital del Mar Medical Research Institute
- Marina Gabriel-Salazar
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Miguel Garcia-Gabilondo
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Ting Lei
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Nuria-Paz Torres-Aguila
- Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU)
- Jara Cárcel-Márquez
- Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU)
- Jerònia Lladó
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Gabriel Olmos
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- Anna Rosell
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Joan Montaner
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Anna M. Planas
- Department of Neuroscience and Experimental Therapeutics, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC)
- Raquel Rabionet
- Department of Genetics, Microbiology & Statistics, IBUB, University of Barcelona (UB)
- Mar Hernández-Guillamon
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona
- Jordi Jiménez-Conde
- Neurology, Hospital del Mar Medical Research Institute
- Israel Fernández-Cadenas
- Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU)
- Cristòfol Vives-Bauzá
- Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa)
- DOI
- https://doi.org/10.1038/s41420-024-01857-z
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 1 – 13
Abstract
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.