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ヒトiPS細胞由来血管内皮前駆細胞および脳毛細血管内皮細胞の効率的な分化誘導法の開発

青木 啓将 Aoki Hiromasa 名古屋市立大学

2020.03.25

概要

脳毛細血管内皮細胞 (BMECs)、ペリサイト、アストロサイトなどから構成される血液脳関門 (BBB) (Figure 1) は、医薬品やサイトカインなど様々な物質の脳側への移行を制御する役割を担っている。その強固なバリア機能が障害となり、中枢神経系を標的とした新薬候補化合物が脳実質まで到達せず開発が中止となる場合が多い。また、アルツハイマーやパーキンソン病などの中枢神経系の変性疾患と BBB の恒常性の破綻が密接な関連性を持つことも明らかとなってきている。このような背景から、BBB における薬物透過性や BBB の恒常性の破綻と関連する病態を、簡易的かつ正確に解析できるような in vitro BBB モデルの開発が強く望まれている。既存の in vitro ヒト BBB モデルとしてヒト不死化 BMECs や動物 (げっ歯類や霊長類) 由来 BMECs などが知られているが、前者は BBB のバリア機能に不可欠なタイトジャンクション機能が低いこと、後者は性状がヒト BBB と異なるため薬物透過性の正確な予測が困難であることが問題となっている。近年、上記の問題点を克服した細胞を作製しようとする試みがなされており、その一環としてヒト iPS 細胞由来 BMECs (iBMECs) が開発された。この細胞は強固なバリア機能を有している点で他の BBB モデルにおける BMECs よりも優れているが、ヒト iPS細胞から煩雑な工程を経て分化誘導する必要があるため、分化細胞の品質の均一化が困難であり供給面も不安定である。そのため、現段階ではiBMECsを研究機関や製薬企業等で用いる評価モデルの細胞として実用化することは難しい。そこで本研究では、品質や供給面を改善した実用的な in vitro ヒト BBB モデルの確立のため、iBMECs の分化誘導法を最適化することを目的として、以下に示す 2 点について検討を行なった。
1. iBMECs の分化誘導に適した基底膜成分の探索
2. ヒト iPS 細胞由来血管内皮前駆細胞の効率的な分化誘導法・拡大培養法の検討

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