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Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers

We have previously established that the integrity of the induced blood–brain 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 haplo...

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Autores principales: Li, Yunfei, Sun, Zhixiong, Zhu, Huixiang, Sun, Yan, Shteyman, David B., Markx, Sander, Leong, Kam W., Xu, Bin, Fu, Bingmei M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913366/
https://www.ncbi.nlm.nih.gov/pubmed/36766762
http://dx.doi.org/10.3390/cells12030422
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author Li, Yunfei
Sun, Zhixiong
Zhu, Huixiang
Sun, Yan
Shteyman, David B.
Markx, Sander
Leong, Kam W.
Xu, Bin
Fu, Bingmei M.
author_facet Li, Yunfei
Sun, Zhixiong
Zhu, Huixiang
Sun, Yan
Shteyman, David B.
Markx, Sander
Leong, Kam W.
Xu, Bin
Fu, Bingmei M.
author_sort Li, Yunfei
collection PubMed
description We have previously established that the integrity of the induced blood–brain 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’s 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.
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spelling pubmed-99133662023-02-11 Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers Li, Yunfei Sun, Zhixiong Zhu, Huixiang Sun, Yan Shteyman, David B. Markx, Sander Leong, Kam W. Xu, Bin Fu, Bingmei M. Cells Article We have previously established that the integrity of the induced blood–brain 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’s 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. MDPI 2023-01-27 /pmc/articles/PMC9913366/ /pubmed/36766762 http://dx.doi.org/10.3390/cells12030422 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Yunfei
Sun, Zhixiong
Zhu, Huixiang
Sun, Yan
Shteyman, David B.
Markx, Sander
Leong, Kam W.
Xu, Bin
Fu, Bingmei M.
Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
title Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
title_full Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
title_fullStr Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
title_full_unstemmed Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
title_short Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
title_sort inhibition of abl kinase by imatinib can rescue the compromised barrier function of 22q11.2ds patient-ipsc-derived blood–brain barriers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913366/
https://www.ncbi.nlm.nih.gov/pubmed/36766762
http://dx.doi.org/10.3390/cells12030422
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