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

Feb 19, 2024

Experts: 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

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.
© 2024. The Author(s).

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ABOUT THE EXPERTS

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

Aina Medina-Dols

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Guillem Cañellas

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Toni Capó

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Montse Solé

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Marina Mola-Caminal

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Natalia Cullell

Neurology, Hospital Universitari Mútua de Terrassa/Fundacio Docència i Recerca Mútua Terrassa, Terrassa, Spain.

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Marina Jaume

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Laura Nadal-Salas

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Jaume Llinàs

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Lluis Gómez

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Silvia Tur

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Neurology, Hospital Universitari Son Espases (HUSE), Palma, Spain.

Carmen Jiménez

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Neurology, Hospital Universitari Son Espases (HUSE), Palma, Spain.

Rosa M Díaz

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Neurology, Hospital Universitari Son Espases (HUSE), Palma, Spain.

Caty Carrera

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Elena Muiño

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Cristina Gallego-Fabrega

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Carolina Soriano-Tárraga

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Laura Ruiz-Guerra

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Josep Pol-Fuster

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Víctor Asensio

Department of Genetics (GEN-IB), HUSE, IdISBa, Palma, Spain.

Josep Muncunill

Genomic & Bioinformatics Platform, IdISBa, Palma, Spain.

Aarne Fleischer

Genomic & Bioinformatics Platform, IdISBa, Palma, Spain.

Amanda Iglesias

Department of Respiratory Medicine,, Hospital Universitari Son Espases-IdISBa Palma, Spain; CIBERES, Instituto de Salud Carlos III, Madrid, Spain.

CIBER of Respiratory Diseases (CIBERES), Madrid, Spain.

Eva Giralt-Steinhauer

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Uxue Lazcano

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Isabel Fernández-Pérez

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Joan Jiménez-Balado

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Marina Gabriel-Salazar

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Miguel Garcia-Gabilondo

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Ting Lei

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Nuria-Paz Torres-Aguila

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Jara Cárcel-Márquez

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Jerònia Lladó

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Gabriel Olmos

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain.

Anna Rosell

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Joan Montaner

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Institute of Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville & Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain.

Anna M Planas

Department of Neuroscience and Experimental Therapeutics, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.

Area of Neuroscience, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Raquel Rabionet

Department of Genetics, Microbiology & Statistics, IBUB, University of Barcelona (UB), Barcelona, Spain.

Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.

Mar Hernández-Guillamon

Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Jordi Jiménez-Conde

Neurology, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Israel Fernández-Cadenas

Stroke Pharmacogenomics and Genetics, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.

Cristòfol Vives-Bauzá

Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), Palma, Spain. cristofol.vives@uib.cat.

Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), Palma, Spain. cristofol.vives@uib.cat.