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

Tomoko Andoh-Noda, Wado Akamatsu, Kunio Miyake, Takuya Matsumoto, Ryo Yamaguchi, Tsukasa Sanosaka, Yohei Okada, Tetsuro Kobayashi, Manabu Ohyama, Kinichi Nakashima, Hiroshi Kurosawa, Takeo Kubota, Hideyuki Okano

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
JournalMolecular Brain
DOIs
Publication statusAccepted/In press - 2015 May 27

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Multipotent Stem Cells
Rett Syndrome
Neural Stem Cells
Induced Pluripotent Stem Cells
Methyl-CpG-Binding Protein 2
Astrocytes
Glial Fibrillary Acidic Protein
Gene Expression
Genes
Cell Line
Monozygotic Twins
Chromatin Immunoprecipitation
Cell Lineage
Microarray Analysis
Cell Differentiation
Homeostasis
Mutation

Keywords

  • Astrocytes
  • DNA methylation
  • Induced pluripotent stem cell
  • Methyl CpG-binding protein 2/MeCP2
  • Neural stem cell
  • Rett syndrome

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Biology

Cite this

Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage. / Andoh-Noda, Tomoko; Akamatsu, Wado; Miyake, Kunio; Matsumoto, Takuya; Yamaguchi, Ryo; Sanosaka, Tsukasa; Okada, Yohei; Kobayashi, Tetsuro; Ohyama, Manabu; Nakashima, Kinichi; Kurosawa, Hiroshi; Kubota, Takeo; Okano, Hideyuki.

In: Molecular Brain, 27.05.2015.

Research output: Contribution to journalArticle

Andoh-Noda, T, Akamatsu, W, Miyake, K, Matsumoto, T, Yamaguchi, R, Sanosaka, T, Okada, Y, Kobayashi, T, Ohyama, M, Nakashima, K, Kurosawa, H, Kubota, T & Okano, H 2015, 'Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage', Molecular Brain. https://doi.org/10.1186/s13041-015-0121-2
Andoh-Noda, Tomoko ; Akamatsu, Wado ; Miyake, Kunio ; Matsumoto, Takuya ; Yamaguchi, Ryo ; Sanosaka, Tsukasa ; Okada, Yohei ; Kobayashi, Tetsuro ; Ohyama, Manabu ; Nakashima, Kinichi ; Kurosawa, Hiroshi ; Kubota, Takeo ; Okano, Hideyuki. / Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage. In: Molecular Brain. 2015.
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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.",
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AU - Andoh-Noda, Tomoko

AU - Akamatsu, Wado

AU - Miyake, Kunio

AU - Matsumoto, Takuya

AU - Yamaguchi, Ryo

AU - Sanosaka, Tsukasa

AU - Okada, Yohei

AU - Kobayashi, Tetsuro

AU - Ohyama, Manabu

AU - Nakashima, Kinichi

AU - Kurosawa, Hiroshi

AU - Kubota, Takeo

AU - Okano, Hideyuki

PY - 2015/5/27

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N2 - 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.

AB - 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.

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KW - DNA methylation

KW - Induced pluripotent stem cell

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KW - Neural stem cell

KW - Rett syndrome

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