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数理モデル解析による上皮組織及び細胞の化学力学応答の解明

浅倉, 祥文 京都大学 DOI:10.14989/doctor.k23554

2021.09.24

概要

細胞集団運動は初期発生から傷の修復によるホメオスタシス維持まで多様な生命現象を支える重要な現象である。これまでに細胞の増殖、生存とアポトーシス制御、成長、代謝、分化、がん化、そして運動において中心的な制御因子である Extracellular signal-Regulated Kinase (ERK)が上皮組織における細胞集団運動に中心的な役割を果たすことが明らかにされ、さらに上皮組織における細胞集団運動の実験的モデル系である創傷治癒実験において、 Förster /Fluorescence Resonance Energy Transfer (FRET)原理に基づくライブセルイメージング実験により、ERK 活性が組織中を損傷箇所から離れる向きで波として伝播し、細胞は ERK 波に応答して逆向きに傷へと向かって移動することが明らかにされて来た。

細胞集団運動を、定量的な理解のために数理モデルを用いて記述する試みが多数なされてきたが、細胞と組織の力学的な関係性に主眼が置かれ、ERK を含む生化学的なシグナルの作用を組み込み、その上で組織と細胞の関係性を記述した例は無く、細胞のシグナル応答が組織全体の協調的な運動を生み出す機構は未解明であった。

そこで本研究では、ERK 依存的な創傷治癒実験をモデル系とし、この系において細胞の化学力学刺激への応答が組織の動態へ与える影響を記述する数理モデルの構築を目指した。各細胞の ERK 波に対する応答として、細胞の基底膜に占める面積の膨張と細胞の運動能の上昇が観察されていたことから、これらの ERK 応答を各細胞の大きさと摩擦としてモデル化した。そして個々の粒子に対する力学的な作用についてのモデルを粗視化し、連続体としての力学的性質を記述する方程式として、連続体モデルを導出した。

次にこの連続体モデルを、場としての組織に注目したオイラー記述においてシミュレーションし、数値的に解析した。その結果、実際の細胞での観察結果と同様に、細胞の膨張と摩擦の低下が ERK により引き起こされる場合に、ERK 波の進行に対して逆向きの組織運動が生じることが確認された。さらに、組織中の粒子としての細胞に注目したラグランジュ記述において再度シミュレーションを行った。その結果、組織シミュレーションにおいて ERK 波と逆向きの運動が見られた条件では、細胞の軌跡においても ERK 波の進行と逆向きの細胞移動が見られることが確認された。

これらの結果を受け、ERK 波の引き起こすシグナル応答としてモデルに組み込んだ、細胞の占める面積と摩擦の各経路に対応するパラメーターの値をそれぞれ変化させシミュレーションを行うことで、ERK の制御下でエフェクターとして機能する各シグナル経路が ERK 波に応じた組織と細胞の移動にどのように寄与するのか調べた。その結果、細胞の膨張と縮小が移動そのものに必要であることが判り、上記のシミュレーションや先行研究での顕微鏡観察で見られた通り、細胞の膨張と摩擦の低下が ERK により引き起こされる場合に、ERK 波の進行と逆向きの組織と細胞の移動が生じることが判った。

以上のように本研究では化学、力学、組織、細胞という4要素を同時に組み込んだ新たな理論的枠組みを構築した。このモデルは、細胞と組織という異なる階層間にわたる生命現象を定量的に解析することを可能とし、細胞集団運動の解明のための新たな理論手法になると期待される。

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