細胞外マトリクス (ECM) は分解と再構成を繰り返しており，ECM改変に伴う力学特性変化を細胞は感知し，細胞挙動は調節される．力学特性変化に着想を得て，外部刺激に応じて弾性率変化する足場材料が開発されてきた．弾性率変化による短期的な応答は広く研究されているものの，変化前後を考慮した長期的な影響については研究が欠如している．特に，長期に渡り生じるクロマチン構造変化，ひいては細胞老化には，弾性率の履歴が影響を与えうると考えられる．本研究は，光応答性の人工ECMを開発し，細胞が経験する弾性率の時間履歴が記憶としてどのように生成され，老化表現型に影響を及ぼすのかを解明することを目的とする．ノルボルネン-チオール間の光架橋を基盤とする光硬化ゼラチンゲルを用い，弾性率を光で段階的に制御する．これにより，記憶の保持時間や臨界振幅を指標として評価する．Yes-associated proteinの核内移行をはじめ、細胞の力覚機構に関わる種々の細胞評価を統合することで、クロマチン構造変化を介した因果関連を明らかにする．

The extracellular matrix (ECM) undergoes continuous cycles of degradation and remodeling, and cells sense changes in its mechanical properties, thereby regulating their behavior. Inspired by such dynamic mechanical cues, polymeric scaffolds capable of altering their stiffness in response to external stimuli have been developed. While short-term cellular responses to changes in stiffness have been extensively studied, the long-term effects that take into account the history of stiffness changes remain largely unexplored. In particular, it is hypothesized that the temporal history of stiffness may influence chromatin structural changes over extended periods, ultimately affecting cellular senescence.
In this study, we aim to develop a photoresponsive artificial ECM to elucidate how the temporal history of stiffness experienced by cells is remembered and how it influences senescence phenotypes. A photocrosslinkable gelatin hydrogel based on thiol–norbornene chemistry will be employed, enabling stepwise control of stiffness through light irradiation. This system allows quantitative evaluation of memory retention time and critical amplitude as key parameters.
By integrating multiple cellular analyses related to mechanotransduction, including nuclear localization of Yes-associated protein (YAP), we will clarify the causal relationship between mechanical memory and chromatin structural changes that govern cellular senescence.