Actin polymerization inhibition by targeting ARPC2 affects intestinal stem cell homeostasis  

作　　者：Ruzhen Zhang Sheng Chen Zhifan Yang Ning Zhang Kenan Guo Keyi Lv Zimo Zhou Meijiao Gao Xiancheng Hu Yongping Su Jianming He Fengchao Wang 

机构地区：[1]State Key Laboratory of Trauma,Burns and Combined Injury,Institute of Combined Injury,Chongqing Engineering Research Center for Nanomedicine,College of Preventive Medicine,Third Military Medical University,Chongqing 400038,China [2]College of Life Sciences,Chongqing Normal University,Chongqing,401331 China [3]Department of Laboratory Animal Science,College of Basic Medical Sciences,Army Medical University,Third Military Medical University,Chongqing 400038,China [4]Department of Military Cognitive Psychology,School of Psychology,Third Military Medical University,Chongqing,400038,China [5]Department of Radiotherapy,Hebei Province Hospital of Chinese Medicine,Hebei University of Chinese Medicine,Key Laboratory of Integrated Chinese and Western Medicine for Gastroenterology Research(Hebei),Shijiazhuang,050011

出　　处：《Burns & Trauma》2023年第1期709-721,共13页烧伤与创伤（英文）

基　　金：supported by the National Natural Science Foundation of China(81872556);Chongqing Academician Program(Basic Research and Frontier Exploration)cstc2018jcyj-yszxX0004.

摘　　要：Background:The rapid turnover of the intestinal epithelium is driven by the proliferation and differentiation of intestinal stem cells(ISCs).The dynamics of the F-actin cytoskeleton are critical for maintaining intercellular force and the signal transduction network.However,it remains unclear how direct interference with actin polymerization impacts ISC homeostasis.This study aims to reveal the regulatory effects of the F-actin cytoskeleton on the homeostasis of intestinal epithelium,as well as the potential risks of benproperine(BPP)as an anti-tumor drug.Methods:Phalloidin fluorescence staining was utilized to test F-actin polymerization.Flow cytom-etry and IHC staining were employed to discriminate different types of intestinal epithelial cells.Cell proliferation was assessed through bromo-deoxyuridine(BrdU)and 5-ethynyl-2-deoxyuridine(EdU)incorporation assays.The proliferation and differentiation of intestinal stem cells were replicated in vitro through organoid culture.Epithelial migrationwas evaluated through BrdU pulse labeling and chasing in mice.Results:The F-actin content was observed to significantly increase as crypt cells migrated into the villus region.Additionally,actin polymerization in secretory cells,especially in Paneth cells(PCs),was much higher than that in neighboring ISCs.Treatment with the newly identified actin-related protein 2/3 complex subunit 2(ARPC2)inhibitor BPP led to a dose-dependent increase or inhibition of intestinal organoid growth in vitro and crypt cell proliferation in vivo.Compared with the vehicle group,BPP treatment decreased the expression of Lgr5 ISC feature genes in vivo and in organoid culture.Meanwhile,PC differentiation derived from ISCs and progenitors was decreased by inhibition of F-actin polymerization.Mechanistically,BPP-induced actin polymerization inhibition may activate the Yes1-associated transcriptional regulator pathway,which affects ISC proliferation and differentiation.Accordingly,BPP treatment affected intestinal epithelial cell migration in a dose-dep

关 键 词：F-ACTIN BENPROPERINE ARPC2 Intestinal stem cell YAP 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]