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Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease
Yumi Yamamoto1,2, Katsutoshi Kojima3, Daisuke Taura3
1Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.
Insights
Researchers created an in vitro model for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) using patient-derived cells. This model successfully replicates key CADASIL pathologies, aiding in understanding the disease and developing treatments.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease linked to NOTCH3 mutations.
- Previous studies identified specific protein deposits and increased PDGFRβ in CADASIL postmortem brains.
Purpose of the Study:
- To establish an in vitro model of CADASIL using induced pluripotent stem cells (iPSCs).
- To recapitulate CADASIL-specific phenotypes in patient-derived mural cells (MCs).
Main Methods:
- Differentiated iPSCs from three CADASIL patients (with specific NOTCH3 mutations) into mature MCs.
- Analyzed MCs for functional and molecular profiles, including PDGFRβ expression, actin structure, and N3ECD/LTBP-1/HtrA1 deposits.
- Assessed MC migration rates and reactivity to PDGF-BB.
Main Results:
- CADASIL MCs exhibited increased PDGFRβ, abnormal actin networks, and pathogenic deposits, mirroring postmortem findings.
- Migration rates of CADASIL MCs were enhanced but reduced upon NOTCH3 or PDGFRB knockdown.
- CADASIL MCs displayed altered responses to PDGF-BB.
Conclusions:
- Patient-derived MCs effectively recapitulate CADASIL pathology in vitro.
- This iPSC-based model is valuable for studying CADASIL pathogenesis.
- The model offers a platform for developing novel therapeutic strategies for CADASIL.
Abstract:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary cerebral small vessel diseases and is caused by mutations in NOTCH3. Our group has previously reported incorporation of NOTCH3 extracellular domain (N3ECD) in the CADASIL-specific granular osmiophilic materials and increase of PDGFRβ immunoreactivity in CADASIL postmortem brains. Here, we aimed to establish an in vitro model of CADASIL, which can recapitulate those CADASIL phenotypes, using induced pluripotent stem cells (iPSCs). We have refined a differentiation protocol of endothelial cells to obtain mature mural cells (MCs) with their characteristic properties. iPSCs from three CADASIL patients with p.Arg182Cys, p.Arg141Cys and p.Cys106Arg mutations were differentiated into MCs and their functional and molecular profiles were compared. The differentiated CADASIL MCs recapitulated pathogenic changes reported previously: increased PDGFRβ and abnormal structure/distribution of filamentous actin network, as well as N3ECD/LTBP-1/HtrA1-immunopositive deposits. Migration rate of CADASIL MCs was enhanced but suppressed by knockdown of NOTCH3 or PDGFRB. CADASIL MCs showed altered reactivity to PDGF-BB. Patient-derived MCs can recapitulate CADASIL pathology and are therefore useful in understanding the pathogenesis and developing potential treatment strategies.
