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Mol Brain. 2015 May 27;8:31. doi: 10.1186/s13041-015-0121-2.

Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage.

Author information

1
Division of Medicine and Engineering Science, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 4-4-37 Takeda, Yamanashi, Kofu, 400-8510, Japan. t.nodando@a7.keio.jp.
2
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. t.nodando@a7.keio.jp.
3
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. awado@juntendo.ac.jp.
4
Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. awado@juntendo.ac.jp.
5
Department of Epigenetic Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. kmiyake@yamanashi.ac.jp.
6
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. tak560924@gmail.com.
7
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. ryo-yamaguchi@ds-pharma.co.jp.
8
Sumitomo Dainipponn Pharma Co. Ltd., Osaka, Osaka, 541-0045, Japan. ryo-yamaguchi@ds-pharma.co.jp.
9
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. sanosaka@z8.keio.jp.
10
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. yohei@aichi-med-u.ac.jp.
11
Department of Neurology,School of Meidicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan. yohei@aichi-med-u.ac.jp.
12
Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. tetsuro.koba0420@gmail.com.
13
Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. manabuohy@z8.keio.jp.
14
Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. kin1@scb.med.kyushu-u.ac.jp.
15
Division of Medicine and Engineering Science, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 4-4-37 Takeda, Yamanashi, Kofu, 400-8510, Japan. kurohiro@yamanashi.ac.jp.
16
Department of Epigenetic Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. takeot@yamanashi.ac.jp.
17
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,Shinjuku-ku, Tokyo, 160-8582, Japan. hidokano@a2.keio.jp.

Abstract

BACKGROUND:

Rett syndrome (RTT) is one of the most prevalent neurodevelopmental disorders in females, caused by de novo mutations in the X-linked methyl CpG-binding protein 2 gene, MECP2. Although abnormal regulation of neuronal genes due to mutant MeCP2 is thought to induce autistic behavior and impaired development in RTT patients, precise cellular mechanisms underlying the aberrant neural progression remain unclear.

RESULTS:

Two sets of isogenic pairs of either wild-type or mutant MECP2-expressing human induced pluripotent stem cell (hiPSC) lines were generated from a single pair of 10-year-old RTT-monozygotic (MZ) female twins. Mutant MeCP2-expressing hiPSC lines did not express detectable MeCP2 protein during any stage of differentiation. The lack of MeCP2 reflected altered gene expression patterns in differentiated neural cells rather than in undifferentiated hiPSCs, as assessed by microarray analysis. Furthermore, MeCP2 deficiency in the neural cell lineage increased astrocyte-specific differentiation from multipotent neural stem cells. Additionally, chromatin immunoprecipitation (ChIP) and bisulfite sequencing assays indicated that anomalous glial fibrillary acidic protein gene (GFAP) expression in the MeCP2-negative, differentiated neural cells resulted from the absence of MeCP2 binding to the GFAP gene.

CONCLUSIONS:

An isogenic RTT-hiPSC model demonstrated that MeCP2 participates in the differentiation of neural cells. Moreover, MeCP2 deficiency triggers perturbation of astrocytic gene expression, yielding accelerated astrocyte formation from RTT-hiPSC-derived neural stem cells. These findings are likely to shed new light on astrocytic abnormalities in RTT, and suggest that astrocytes, which are required for neuronal homeostasis and function, might be a new target of RTT therapy.

PMID:
26012557
PMCID:
PMC4446051
DOI:
10.1186/s13041-015-0121-2
[Indexed for MEDLINE]
Free PMC Article

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