Actin polymerization inhibition by targeting ARPC2 affects intestinal stem cell homeostasis
- Burns & Trauma Vol. 11, Issue 1, (2023)
- 作者机构：
1. Third Military Medical University
2. Chongqing Normal University
3. Hebei University of Chinese Medicine, Key Laboratory of Integrated Chinese and Western Medicine for Gastroenterology Research,Hebei
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkad038
CLC：Published：2023，
Published Online：16 October 2023，
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Ruzhen Zhang, Sheng Chen, Zhifan Yang, Ning Zhang, Kenan Guo, Keyi Lv, Zimo Zhou, Meijiao Gao, Xiancheng Hu, Yongping Su, Jianming He, Fengchao Wang, Actin polymerization inhibition by targeting ARPC2 affects intestinal stem cell homeostasis, Burns & Trauma, Volume 11, 2023, tkad038, https://doi.org/10.1093/burnst/tkad038
Ruzhen Zhang, Sheng Chen, Zhifan Yang, Ning Zhang, Kenan Guo, Keyi Lv, Zimo Zhou, Meijiao Gao, Xiancheng Hu, Yongping Su, Jianming He, Fengchao Wang, Actin polymerization inhibition by targeting ARPC2 affects intestinal stem cell homeostasis, Burns & Trauma, Volume 11, 2023, tkad038, https://doi.org/10.1093/burnst/tkad038 DOI：
摘要
Abstract
BackgroundThe 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.MethodsPhalloidin fluorescence staining was utilized to test F-actin polymerization. Flow cytometry 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 migration was evaluated through BrdU pulse labeling and chasing in mice.ResultsThe 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-dependent manner.ConclusionOur findings indicate that the regulation of cytoskeleton reorganization can affect ISC homeostasis. In addition
inhibiting ARPC2 with the Food and Drug Administration-approved drug BPP represents a novel approach to influencing the turnover of intestinal epithelial cells.
关键词
Keywords
F-actinBenproperineARPC2Intestinal stem cellYAP
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