In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling

Kohei Yamamizu, Mio Iwasaki, Hitomi Takakubo, Takumi Sakamoto, Takeshi Ikuno, Mami Miyoshi, Takayuki Kondo, Youichi Nakao, Masato Nakagawa, Haruhisa Inoue, Jun K. Yamashita

    Research output: Contribution to journalArticle

    28 Citations (Scopus)

    Abstract

    The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.

    Original languageEnglish
    Pages (from-to)634-647
    Number of pages14
    JournalStem Cell Reports
    Volume8
    Issue number3
    DOIs
    Publication statusPublished - 2017 Mar 14

    Fingerprint

    Pericytes
    Endothelial cells
    Blood-Brain Barrier
    Astrocytes
    Neurons
    Endothelial Cells
    Brain
    Induced Pluripotent Stem Cells
    Permeability
    Population
    Tight Junctions
    Physiology
    Pathology
    Stem cells
    Pharmaceutical Preparations
    Nutrients
    Cultured Cells
    Cells
    Technology
    Specifications

    Keywords

    • astrocytes
    • blood-brain barrier
    • drug kinetics
    • endothelial cells
    • induced pluripotent stem cells
    • neurons
    • Notch signaling
    • pericytes
    • permeability
    • vasculature

    ASJC Scopus subject areas

    • Biochemistry
    • Genetics
    • Developmental Biology
    • Cell Biology

    Cite this

    In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling. / Yamamizu, Kohei; Iwasaki, Mio; Takakubo, Hitomi; Sakamoto, Takumi; Ikuno, Takeshi; Miyoshi, Mami; Kondo, Takayuki; Nakao, Youichi; Nakagawa, Masato; Inoue, Haruhisa; Yamashita, Jun K.

    In: Stem Cell Reports, Vol. 8, No. 3, 14.03.2017, p. 634-647.

    Research output: Contribution to journalArticle

    Yamamizu, K, Iwasaki, M, Takakubo, H, Sakamoto, T, Ikuno, T, Miyoshi, M, Kondo, T, Nakao, Y, Nakagawa, M, Inoue, H & Yamashita, JK 2017, 'In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling', Stem Cell Reports, vol. 8, no. 3, pp. 634-647. https://doi.org/10.1016/j.stemcr.2017.01.023
    Yamamizu, Kohei ; Iwasaki, Mio ; Takakubo, Hitomi ; Sakamoto, Takumi ; Ikuno, Takeshi ; Miyoshi, Mami ; Kondo, Takayuki ; Nakao, Youichi ; Nakagawa, Masato ; Inoue, Haruhisa ; Yamashita, Jun K. / In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling. In: Stem Cell Reports. 2017 ; Vol. 8, No. 3. pp. 634-647.
    @article{8ce5157cf45e4ee89d4dcdc01bb99360,
    title = "In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling",
    abstract = "The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.",
    keywords = "astrocytes, blood-brain barrier, drug kinetics, endothelial cells, induced pluripotent stem cells, neurons, Notch signaling, pericytes, permeability, vasculature",
    author = "Kohei Yamamizu and Mio Iwasaki and Hitomi Takakubo and Takumi Sakamoto and Takeshi Ikuno and Mami Miyoshi and Takayuki Kondo and Youichi Nakao and Masato Nakagawa and Haruhisa Inoue and Yamashita, {Jun K.}",
    year = "2017",
    month = "3",
    day = "14",
    doi = "10.1016/j.stemcr.2017.01.023",
    language = "English",
    volume = "8",
    pages = "634--647",
    journal = "Stem Cell Reports",
    issn = "2213-6711",
    publisher = "Cell Press",
    number = "3",

    }

    TY - JOUR

    T1 - In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling

    AU - Yamamizu, Kohei

    AU - Iwasaki, Mio

    AU - Takakubo, Hitomi

    AU - Sakamoto, Takumi

    AU - Ikuno, Takeshi

    AU - Miyoshi, Mami

    AU - Kondo, Takayuki

    AU - Nakao, Youichi

    AU - Nakagawa, Masato

    AU - Inoue, Haruhisa

    AU - Yamashita, Jun K.

    PY - 2017/3/14

    Y1 - 2017/3/14

    N2 - The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.

    AB - The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.

    KW - astrocytes

    KW - blood-brain barrier

    KW - drug kinetics

    KW - endothelial cells

    KW - induced pluripotent stem cells

    KW - neurons

    KW - Notch signaling

    KW - pericytes

    KW - permeability

    KW - vasculature

    UR - http://www.scopus.com/inward/record.url?scp=85013669628&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85013669628&partnerID=8YFLogxK

    U2 - 10.1016/j.stemcr.2017.01.023

    DO - 10.1016/j.stemcr.2017.01.023

    M3 - Article

    C2 - 28238797

    AN - SCOPUS:85013669628

    VL - 8

    SP - 634

    EP - 647

    JO - Stem Cell Reports

    JF - Stem Cell Reports

    SN - 2213-6711

    IS - 3

    ER -