Single-cell sequencing reveals that endothelial cells, EndMT cells and mural cells contribute to the pathogenesis of cavernous malformations
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Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
Jian Ren1, Xiao Xiao2, Ruofei Li2
1Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute, Beijing, China.
Insights
Researchers identified a new endothelial cell (EC) subpopulation in human cavernous malformations (CMs) and discovered endothelial-to-mesenchymal transition (EndMT) cells, offering new therapeutic targets for CM disease.
Area of Science:
- Neuroscience
- Vascular Biology
- Genetics
Background:
- Cavernous malformations (CMs) are vascular anomalies in the central nervous system, often causing hemorrhages and neurological deficits.
- Understanding CM pathogenesis is crucial for developing effective therapeutic strategies.
- Human CM studies are essential for advancing disease mechanism knowledge.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms underlying human CMs.
- To identify novel cell types and pathways involved in CM development.
- To provide insights for precise therapeutic interventions in CMs.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of human CM samples and controls.
- Cellular ligand-receptor network analysis.
- In vitro and in vivo validation of identified pathways and cell behaviors.
Main Results:
- Identification of a novel PLVAP-positive endothelial cell (EC) subpopulation in CM lesions.
- PLVAP+ ECs are key drivers of ANGPT and VEGF signaling, with activated PI3K/AKT/mTOR pathway.
- First identification of endothelial-to-mesenchymal transition (EndMT) cells in CMs, linked to immune activation and driven by SPI1.
- Smooth muscle cells exhibit a fibroblast-like phenotype, modulated by TWIST1, suggesting roles in vessel repair.
Conclusions:
- Novel insights into CM pathomechanisms through single-cell analysis.
- Identification of PLVAP+ ECs and EndMT as critical players in CM pathogenesis.
- SPI1 and TWIST1 emerge as potential therapeutic targets for CMs.
Abstract:
Cavernous malformations (CMs) invading the central nervous system occur in ~0.16-0.4% of the general population, often resulting in hemorrhages and focal neurological deficits. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of CMs in humans. Herein, we performed single-cell RNA sequencing (scRNA-seq) analysis on unselected viable cells from twelve human CM samples and three control samples. A total of 112,670 high-quality cells were clustered into 11 major cell types, which shared a number of common features in CMs harboring different genetic mutations. A new EC subpopulation marked with PLVAP was uniquely identified in lesions. The cellular ligand‒receptor network revealed that the PLVAP-positive EC subcluster was the strongest contributor to the ANGPT and VEGF signaling pathways in all cell types. The PI3K/AKT/mTOR pathway was strongly activated in the PLVAP-positive subcluster even in non-PIK3CA mutation carriers. Moreover, endothelial-to-mesenchymal transition (EndMT) cells were identified for the first time in CMs at the single-cell level, which was accompanied by strong immune activation. The transcription factor SPI1 was predicted to be a novel key driver of EndMT, which was confirmed by in vitro and in vivo studies. A specific fibroblast-like phenotype was more prevalent in lesion smooth muscle cells, hinting at the role of vessel reconstructions and repairs in CMs, and we also confirmed that TWIST1 could induce SMC phenotypic switching in vitro and in vivo. Our results provide novel insights into the pathomechanism decryption and further precise therapy of CMs.
