{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:49:29Z","timestamp":1760147369997,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1UG3UH3TR002151"],"award-info":[{"award-number":["1UG3UH3TR002151"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We have previously established that the integrity of the induced blood\u2013brain barrier (iBBB) formed by brain microvascular endothelial cells derived from the iPSC of 22q11.2 DS (22q11.2 Deletion Syndrome, also called DiGeorge Syndrome) patients is compromised. We tested the possibility that the haploinsufficiency of CRKL, a gene within the 22q11.2 DS deletion region, contributes to the deficit. The CRKL is a major substrate of the Abl tyrosine kinase, and the Abl\/CRKL signaling pathway is critical for endothelial barrier functions. Imatinib, an FDA-approved drug, inhibits Abl kinase and has been used to treat various disorders involving vascular leakages. To test if imatinib can restore the compromised iBBB, we treated the patient\u2019s iBBB with imatinib. After treatment, both trans-endothelial electrical resistance and solute permeability returned to comparable levels of the control iBBB. Correspondingly, changes in tight junctions and endothelial glycocalyx of the iBBB were also restored. Western blotting showed that imatinib increased the level of active forms of the CRKL protein. A transcriptome study revealed that imatinib up-regulated genes in the signaling pathways responsible for the protein modification process and down-regulated those for cell cycling. The KEGG pathway analysis further suggested that imatinib improved the gene expression of the CRKL signaling pathway and tight junctions, which agrees with our expectations and the observations at protein levels. Our results indicate that the 22q11.2DS iBBB is at least partially caused by the haploinsufficiency of CRKL, which can be rescued by imatinib via its effects on the Abl\/CRKL signaling pathway. Our findings uncover a novel disease mechanism associated with 22q11.2DS.<\/jats:p>","DOI":"10.3390\/cells12030422","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T07:56:48Z","timestamp":1675065408000},"page":"422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood\u2013Brain Barriers"],"prefix":"10.3390","volume":"12","author":[{"given":"Yunfei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-1660","authenticated-orcid":false,"given":"Zhixiong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huixiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David B.","family":"Shteyman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sander","family":"Markx","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kam W.","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-5895","authenticated-orcid":false,"given":"Bingmei M.","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/mgg3.310","article-title":"Pediatric healthcare costs for patients with 22q11.2 deletion syndrome","volume":"5","author":"Benn","year":"2017","journal-title":"Mol. 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