Varying mechanical forces drive sensory epithelium formation

Mingyu Xia; Mingxuan Wu; Yuanrong Li; Yaoqian Liu; Gaogan Jia; Yiyun Lou; Jiaoyao Ma; Qing Gao; Mingjun Xie; Yuewei Chen; Yong He; Huawei Li; Wenyan Li

doi:10.1126/sciadv.adf2664

Varying mechanical forces drive sensory epithelium formation

Sci Adv. 2023 Nov 3;9(44):eadf2664. doi: 10.1126/sciadv.adf2664. Epub 2023 Nov 3.

Authors

Mingyu Xia^{1

2

3

4}, Mingxuan Wu^{1

2}, Yuanrong Li^{5

6

7}, Yaoqian Liu^{1

2}, Gaogan Jia^{1

2}, Yiyun Lou^{1

2}, Jiaoyao Ma^{1

2}, Qing Gao^{5

6}, Mingjun Xie^{5

6

8}, Yuewei Chen^{5

6}, Yong He^{5

6

7}, Huawei Li^{1

2

3

4

9}, Wenyan Li^{1

2

3

4}

Affiliations

¹ ENT institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
² Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
³ NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.
⁴ The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
⁵ State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou 310027, China.
⁶ Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province, School of Mechanical Engineering, Zhejiang University, Hangzhou 310027, China.
⁷ Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
⁸ Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
⁹ Shanghai Engineering Research Centre of Cochlear Implant, Shanghai 200031, China.

Abstract

The mechanical cues of the external microenvironment have been recognized as essential clues driving cell behavior. Although intracellular signals modulating cell fate during sensory epithelium development is well understood, the driving force of sensory epithelium formation remains elusive. Here, we manufactured a hybrid hydrogel with tunable mechanical properties for the cochlear organoids culture and revealed that the extracellular matrix (ECM) drives sensory epithelium formation through shifting stiffness in a stage-dependent pattern. As the driving force, moderate ECM stiffness activated the expansion of cochlear progenitor cell (CPC)-derived epithelial organoids by modulating the integrin α3 (ITGA3)/F-actin cytoskeleton/YAP signaling. Higher stiffness induced the transition of CPCs into sensory hair cells (HCs) through increasing the intracellular Ca²⁺ signaling mediated by PIEZO2 and then activating KLF2 to accomplish the cell specification . Our results identify the molecular mechanism of sensory epithelium formation guided by ECM mechanical force and contribute to developing therapeutic approaches for HC regeneration.

MeSH terms

Actin Cytoskeleton
Cell Differentiation
Epithelium
Extracellular Matrix*
Signal Transduction*