Zonated mechanosensing by PIEZO1 controls liver regeneration

• 成果类型: Article
• 署名作者: Zhang, Ying; Sun, Yuzhuo; Xu, Guangkui; Wu, Yue; Shi, Zhijun; Chang, Zhuo; Liu, Junjun; Pang, Kaidan; Liu, Siyu; Wang, Han; Rong, Weixin; Shao, Zehua; Liu, Xingqian; He, Yu; Yan, Yang; Zhou, Bin; Yuan, Zuyi; Zhang, Xu-Feng; Offermanns, Stefan; Wang, Shengpeng
• 署名单位: Xi'an Jiaotong University; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; University of Chinese Academy of Sciences, CAS; Max Planck Society; Goethe University Frankfurt
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aef0825
• 发表日期: 2026-07-02
• 页码: eaef0825
• 关键词: cell-division; stem-cells; hepatocytes; homeostasis; architecture; yap

摘要

The liver exhibits a marked regenerative capacity organized through distinct zones, yet how tissue mechanics coordinate zonated proliferation remains elusive. We reveal that mechanical cues critically contribute to mouse liver regeneration in a highly region-specific manner through sensing by a subpopulation of mid-lobular hepatocytes, which are characterized by dipeptidyl peptidase-4 (DPP4) expression and represent the key proliferative pool of hepatocytes. PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4+ hepatocytes that integrates biomechanical cues to drive liver regrowth by insulin-like growth factor binding protein 2 (IGFBP2). Genetic disruption of PIEZO1 restrains hepatocyte proliferation and compromises liver regeneration, whereas zonated PIEZO1 gain of function enhances proliferation and accelerates recovery. These findings reveal that DPP4+ mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing, establishing a link between tissue mechanics and liver regeneration.