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Endothelial Differentiation of CCM1 Knockout iPSCs Triggers the Establishment of a Specific Gene Expression Signature
- Cerebral cavernous malformation (CCM) is a neurovascular disease that can lead to seizures and stroke-like symptoms. The familial form is caused by a heterozygous germline mutation in either the CCM1, CCM2, or CCM3 gene. While the importance of a second-hit mechanism in CCM development is well established, it is still unclear whether it immediately triggers CCM development or whether additional external factors are required. We here used RNA sequencing to study differential gene expression in CCM1 knockout induced pluripotent stem cells (CCM1−/− iPSCs), early mesoderm progenitor cells (eMPCs), and endothelial-like cells (ECs). Notably, CRISPR/Cas9-mediated inactivation of CCM1 led to hardly any gene expression differences in iPSCs and eMPCs. However, after differentiation into ECs, we found the significant deregulation of signaling pathways well known to be involved in CCM pathogenesis. These data suggest that a microenvironment of proangiogenic cytokines and growth factors can trigger the establishment of a characteristic gene expression signature upon CCM1 inactivation. Consequently, CCM1−/− precursor cells may exist that remain silent until entering the endothelial lineage. Collectively, not only downstream consequences of CCM1 ablation but also supporting factors must be addressed in CCM therapy development.
Author: | Robin A. Pilz, Dariush Skowronek, Lara Mellinger, Sander BekeschusORCiD, Ute Felbor, Matthias Rath |
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URN: | urn:nbn:de:gbv:9-opus-79311 |
DOI: | https://doi.org/10.3390/ijms24043993 |
ISSN: | 1422-0067 |
Parent Title (English): | International Journal of Molecular Sciences |
Publisher: | MDPI |
Place of publication: | Basel |
Document Type: | Article |
Language: | English |
Date of first Publication: | 2023/02/16 |
Release Date: | 2024/02/02 |
Tag: | CCM1/KRIT1; CRISPR/Cas9 genome editing; RNA-Seq; cerebral cavernous malformation; endothelial-specific gene expression; iPSC-derived endothelial cells; iPSCs |
Volume: | 24 |
Issue: | 4 |
Article Number: | 3993 |
Page Number: | 14 |
Faculties: | Universitätsmedizin / Institut für Humangenetik |
Collections: | Artikel aus DFG-gefördertem Publikationsfonds |
Licence (German): | Creative Commons - Namensnennung |