3D micropattern force triggers YAP nuclear entry by transport across nuclear pores and modulates stem cells paracrine

Yan Li; Zhenyu Zhong; Cunjing Xu; Xiaodan Wu; Jiaqi Li; Weiyong Tao; Jianglin Wang; Yingying Du; Shengmin Zhang

doi:10.1093/nsr/nwad165

3D micropattern force triggers YAP nuclear entry by transport across nuclear pores and modulates stem cells paracrine

Natl Sci Rev. 2023 Jun 1;10(8):nwad165. doi: 10.1093/nsr/nwad165. eCollection 2023 Aug.

Authors

Yan Li^{1

2}, Zhenyu Zhong^{1

2}, Cunjing Xu^{1

2}, Xiaodan Wu^{1

2}, Jiaqi Li^{1

2}, Weiyong Tao^{1

2}, Jianglin Wang^{1

2}, Yingying Du^{1

2

3}, Shengmin Zhang^{1

2

3}

Affiliations

¹ Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan430074, China.
² Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan430074, China.
³ Research Base of Regulatory Science for Medical Devices, National Medical Products Administration & Institute of Regulatory Science for Medical Devices, Huazhong University of Science and Technology, Wuhan430074, China.

Abstract

Biophysical cues of the cellular microenvironment tremendously influence cell behavior by mechanotransduction. However, it is still unclear how cells sense and transduce the mechanical signals from 3D geometry to regulate cell function. Here, the mechanotransduction of human mesenchymal stem cells (MSCs) triggered by 3D micropatterns and its effect on the paracrine of MSCs are systematically investigated. Our findings show that 3D micropattern force could influence the spatial reorganization of the cytoskeleton, leading to different local forces which mediate nucleus alteration such as orientation, morphology, expression of Lamin A/C and chromatin condensation. Specifically, in the triangular prism and cuboid micropatterns, the ordered F-actin fibers are distributed over and fully transmit compressive forces to the nucleus, which results in nuclear flattening and stretching of nuclear pores, thus enhancing the nuclear import of YES-associated protein (YAP). Furthermore, the activation of YAP significantly enhances the paracrine of MSCs and upregulates the secretion of angiogenic growth factors. In contrast, the fewer compressive forces on the nucleus in cylinder and cube micropatterns cause less YAP entering the nucleus. The skin repair experiment provides the first in vivo evidence that enhanced MSCs paracrine by 3D geometry significantly promotes tissue regeneration. The current study contributes to understanding the in-depth mechanisms of mechanical signals affecting cell function and provides inspiration for innovative design of biomaterials.

Keywords: 3D micropattern force; bioactive materials; mechanotransduction; paracrine; tissue regeneration.