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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 et al. Cell Death Discovery. 2024 Feb 17;10(1):85. doi: 10.1038/s41420-024-01857-z. PMID: 38368420

https://www.nature.com/articles/s41420-024-01857-z

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.

Funding: This research was funded by Fundació Marató TV3 through the Epigenesis study (188/C/2017), the GENIUS study (307/U/2017) and the GODs study (776/C/2011); by the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III grants PI21/00890 and RICORS Ictus network (RD21/0006/0004, RD21/0006/0007) supported with Next Generation funds; by General Direction of Innovation and Research, Ministry of Innovation, Research and Tourism, Balearic Government, co-funded by European Union ERDF (grant PROCOE/14/2017), and by AGAUR-2021SGR-0656 and AGAUR2021SGR-1093 from Generalitat de Catalunya. AMD and LRG were funded by the FPI fellowship granted by General Direction of Innovation and Research, Ministry of Innovation, Research and Tourism, Balearic Government, co-funded by European Union ERDF. MGG was supported by PERIS-SLT017/20/000197 from AGAUR and TL by the China Scholarship Council (CSC-201706170048).