Cell tumbling enhances stem cell differentiation in hydrogels via nuclear mechanotransduction

Manish Ayushman; Georgios Mikos; Xinming Tong; Sauradeep Sinha; Eunice Lopez-Fuentes; Sarah Jones; Pamela C Cai; Hung-Pang Lee; Ashby J Morrison; Andrew Spakowitz; Sarah C Heilshorn; Alejandro Sweet-Cordero; Fan Yang

doi:10.1038/s41563-024-02038-0

Cell tumbling enhances stem cell differentiation in hydrogels via nuclear mechanotransduction

Nat Mater. 2024 Nov 1. doi: 10.1038/s41563-024-02038-0. Online ahead of print.

Authors

Affiliations

¹ Department of Bioengineering, Stanford University, Stanford, CA, USA.
² Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
³ Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Division of Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁶ Department of Biology, Stanford University, Stanford, CA, USA.
⁷ Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.
⁸ Department of Bioengineering, Stanford University, Stanford, CA, USA. fanyang@stanford.edu.
⁹ Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA. fanyang@stanford.edu.

^# Contributed equally.

PMID: 39487316
DOI: 10.1038/s41563-024-02038-0

Abstract

Cells can deform their local niche in three dimensions via whole-cell movements such as spreading, migration or volume expansion. These behaviours, occurring over hours to days, influence long-term cell fates including differentiation. Here we report a whole-cell movement that occurs in sliding hydrogels at the minutes timescale, termed cell tumbling, characterized by three-dimensional cell dynamics and hydrogel deformation elicited by heightened seconds-to-minutes-scale cytoskeletal and nuclear activity. Studies inhibiting or promoting the cell tumbling of mesenchymal stem cells show that this behaviour enhances differentiation into chondrocytes. Further, it is associated with a decrease in global chromatin accessibility, which is required for enhanced differentiation. Cell tumbling also occurs during differentiation into other lineages and its differentiation-enhancing effects are validated in various hydrogel platforms. Our results establish that cell tumbling is an additional regulator of stem cell differentiation, mediated by rapid niche deformation and nuclear mechanotransduction.