KRIT1 heterozygous mutations are sufficient to induce a pathological phenotype in patient-derived iPSC models of cerebral cavernous malformation

Cerebral cavernous malformation (CCM) is a neurovascular disease distinguished by clusters of leaky, mulberry-like blood vessels. KRIT1 bi-allelic loss-of-function mutations in endothelial cells are known to trigger brain cavernomas; however, human preclinical models are needed to unveil the importance of germline KRIT1 heterozygous mutations in CCM pathogenesis. We generated three induced pluripotent stem cells (iPSCs) from patients with CCM with hereditary KRIT1 heterozygous mutations. Patient-derived vascularized organoids exhibited intricate and abnormal vascular structures with cavernoma-like morphology, and iPSC-derived endothelial cells displayed phenotypic abnormalities at the junctional and transcriptional levels. Upon injection into brain explants, CCM endothelial cells integrated into the normal vasculature and created vascular anomalies. Lastly, transcriptional analysis showed that the endothelial progenitor marker paternally expressed gene 3 (PEG3) was highly expressed in iPSC-derived CCM endothelial cells, and this was further confirmed in familial and sporadic cavernoma biopsies. Overall, our study sheds light on the molecular consequence of KRIT1 heterozygous mutations in endothelial cells and the potential implications in cavernoma pathogenesis.

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Publication Details

Journal
Cell Reports
Published
2025-04-14
DOI
https://doi.org/10.1016/j.celrep.2025.115576
Citations
7
Primary Topic
Vascular Malformations Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
9.72
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article

KRIT1 heterozygous mutations are sufficient to induce a pathological phenotype in patient-derived iPSC models of cerebral cavernous malformation

Francesca Lazzaroni, Anna Dimberg, Mika Niemelä, Peetra U. Magnusson et al.
7 citations
Cell Reports
Vascular Malformations Diagnosis and Treatment
9.72
article

KRIT1 heterozygous mutations are sufficient to induce a pathological phenotype in patient-derived iPSC models of cerebral cavernous malformation

Francesca Lazzaroni, Anna Dimberg, Mika Niemelä, Peetra U. Magnusson, Behnam Rezai Jahromi, Dario Ronchi, Roberto Latini, Mark Richards, Elisa Scola, Jens Schuster, Monica Corada, N. Senthilkumar, Roberta Lugano, Fan Yang, Niklas Dahl, Favour Chinyere Onyeogaziri, Maximiliano Arce, Iza Erzar, Linda Meggiolaro, Silvia Lanfraconi, Frida C Ahlstrand, Nora Noll
article en
7 citations

Abstract

Cerebral cavernous malformation (CCM) is a neurovascular disease distinguished by clusters of leaky, mulberry-like blood vessels. KRIT1 bi-allelic loss-of-function mutations in endothelial cells are known to trigger brain cavernomas; however, human preclinical models are needed to unveil the importance of germline KRIT1 heterozygous mutations in CCM pathogenesis. We generated three induced pluripotent stem cells (iPSCs) from patients with CCM with hereditary KRIT1 heterozygous mutations. Patient-derived vascularized organoids exhibited intricate and abnormal vascular structures with cavernoma-like morphology, and iPSC-derived endothelial cells displayed phenotypic abnormalities at the junctional and transcriptional levels. Upon injection into brain explants, CCM endothelial cells integrated into the normal vasculature and created vascular anomalies. Lastly, transcriptional analysis showed that the endothelial progenitor marker paternally expressed gene 3 (PEG3) was highly expressed in iPSC-derived CCM endothelial cells, and this was further confirmed in familial and sporadic cavernoma biopsies. Overall, our study sheds light on the molecular consequence of KRIT1 heterozygous mutations in endothelial cells and the potential implications in cavernoma pathogenesis.

Cell ReportsVol. 44(5)
University of Helsinki (FI), Mario Negri Institute for Pharmacological Research (IT), Science for Life Laboratory (SE), Helsinki University Hospital (FI), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Manchester (GB), Henry Royce Institute (GB), Ospedale Maggiore (IT), IFOM (IT)
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Vascular Malformations Diagnosis and Treatment
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