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March 30, 2020

A new model for a rare disease that causes strokes

The Inoue laboratory uses iPS cell reprogramming to make a new cellular model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a congenital disease that increases the risk of stroke. By differentiating CADASIL patient iPS cells into mural cells, which are a cell type critically affected by the disease, the researchers recapitulated the phenotypes seen in patients, suggesting the potential of this model for both studying the disease development and for developing preventative or curative treatments. The study can be read in Molecular Brain (doi: 10.1186/s13041-020-00573-w).

A stroke describes blood flow to the brain that is disrupted. While the outcome is brain damage, the cause is attributed to defects in blood vessels, either as physical damage to the vessels that causes bleeding or abnormal blood flow dynamics due to clots. Age is the biggest risk factor for strokes, and lifestyle changes including diet and exercise are highly recommended to older populations at high risk.

However, several hereditary diseases such as CADASIL leave patients at risk from birth, and it is not unusual for patients to experience multiple strokes in their lifetime. While the blood vessels may recover functionally, the brain damage often does not, compounding the risk of dementia and personality disorders.

Mutations in one gene, NOTCH3, are associated with all cases of CADASIL, and the gene especially affects mural cells, which are found in small blood vessels.

The Inoue laboratory prepared iPS cells from three CADASIL patients, each with a distinctive NOTCH3 mutation. Differentiating the iPS cells into mural cells revealed phenotypes typically seen in the mural cells of CADASIL patients, including changes to the cytoskeleton network, which led to changes in the migration rate of mural cells. Further study molecular causes including changes to the expression level of PDGFRβ, a cell surface receptor that regulates angiogenesis.

Paper Details
  • Journal: Molecular Brain
  • Title: Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease
  • Authors: Yumi Yamamoto, Katsutoshi Kojima, Daisuke Taura, Masakatsu Sone, Kazuo Washida, Naohiro Egawa, Takayuki Kondo, Eiko N. Minakawa, Kayoko Tsukita, Takako Enami, Hidekazu Tomimoto, Toshiki Mizuno, Raj N. Kalaria, Nobuya Inagaki, Ryosuke Takahashi, Mariko Harada-Shiba, Masafumi Ihara and Haruhisa Inoue
  • Author Affiliations:
    1. Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan Yumi Yamamoto
    2. Department of Molecular Innovation in Lipidemiology, National Cerebral and Cardiovascular Center Research Institute Yumi Yamamoto & Mariko Harada-Shiba
    3. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University Katsutoshi Kojima, Daisuke Taura, Masakatsu Sone & Nobuya Inagaki
    4. Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center Kazuo Washida & Masafumi Ihara
    5. Center for iPS Cell Research and Application (CiRA), Kyoto University Naohiro Egawa, Takayuki Kondo, Kayoko Tsukita, Takako Enami & Haruhisa Inoue
    6. iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC) Naohiro Egawa, Takayuki Kondo, Kayoko Tsukita & Haruhisa Inoue
    7. Department of Neurology, Kyoto University Graduate School of Medicine Naohiro Egawa & Ryosuke Takahashi
    8. Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP) Takayuki Kondo, Takako Enami & Haruhisa Inoue
    9. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry Eiko N. Minakawa
    10. Department of Dementia Prevention and Therapeutics, Graduate School of Medicine, Mie University Hidekazu Tomimoto
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