Cell migration in confining microenvironments is limited by the ability of the stiff nucleus to deform through pores when migration paths are preexisting and elastic, but how cells generate these paths remains unclear. Here, we reveal a mechanism by which the nucleus mechanically generates migration paths for mesenchymal stem cells (MSCs) in confining microenvironments. MSCs migrate robustly in nanoporous, confining hydrogels that are viscoelastic and plastic but not in hydrogels that are more elastic. To migrate, MSCs first extend thin protrusions that widen over time because of a nuclear piston, thus opening up a migration path in a confining matrix. Theoretical modeling and experiments indicate that the nucleus pushing into the protrusion activates mechanosensitive ion channels, leading to an influx of ions that increases osmotic pressure, which outcompetes hydrostatic pressure to drive protrusion expansion. Thus, instead of limiting migration, the nucleus powers migration by generating migration paths.

当迁移路径预先存在且具有弹性时，细胞在封闭微环境中的迁移受到硬核通过孔变形的能力的限制，但细胞如何产生这些路径仍不清楚。在这里，我们揭示了一种机制，通过该机制，细胞核在受限微环境中机械地为间充质干细胞 (MSC) 生成迁移路径。MSC 在粘弹性和塑性的纳米多孔、封闭水凝胶中稳健迁移，但在更具弹性的水凝胶中则不会。为了迁移，MSC 首先延伸细小的突起，这些突起会因核活塞而随着时间的推移而变宽，从而在限制矩阵中开辟一条迁移路径。理论模型和实验表明，核推入突起会激活机械敏感离子通道，导致离子流入，从而增加渗透压，它胜过静水压力以驱动突出物膨胀。因此，核不是限制迁移，而是通过生成迁移路径来为迁移提供动力。