ATN-161 alleviates caerulein-induced pancreatitis  

作　　者：Rong-rong Gao Lan-yue Ma Jian-wei Chen Yu-xiang Wang Yu-yan Li Zi-yuan Zhou Zhao-hua Deng Jing Zhong Ya-hai Shu Yang Liu Qi Chen 

机构地区：[1]Biomedical Sciences College&Shandong Medicinal Biotechnology Centre,Shandong First Medical University&Shandong Academy of Medical Sciences,NHC Key Laboratory of Biotechnology Drugs(Shandong Academy of Medical Sciences),Key Lab for Rare&Uncommon Diseases of Shandong Province,Ji’nan,Shandong 250117,China [2]Center for Cell Lineage Atlas,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,Guangdong 510530,China [3]University of Chinese Academy of Sciences,Beijing 101408,China [4]China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,Guangdong 510530,China [5]Institutes of Physical Science and Information Technology,Anhui University,Hefei,Anhui 230601,China [6]National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Shenzhen,Guangdong 518116,China [7]The Innovation Centre of Ministry of Education for Development and Diseases,School of Medicine,South China University of Technology,Guangzhou,Guangdong 510006,China [8]Joint School of Life Sciences,Guangzhou Medical University,Guangzhou,Guangdong 511436,China

出　　处：《Journal of Genetics and Genomics》2024年第12期1447-1458,共12页遗传学报（英文版）

基　　金：supported by the National Key R&D Program of China(2022YFA1103200);the Fundamental Research Funds for the Central Universities(2024ZYGXZR077);National Natural Science Foundation of China(32270866,32300693,32471155,3247086822107045);Guangzhou basic and applied basic research funding(2024A04J6259);The Pearl River Talent Recruitment Program(2023ZT10Y154,2021ZT09Y233,2023QN10Y147);South China University of Technology(D6241240);Talent Program and Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences(1103792101,GIBHBRP23-02,GIBHBRP24-01);Cooperation Fund of CHCAMS and SZCH(E010221005,CFA202201006);Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences(KLRB202201,KLRB202305);partially supported by Science and Technology Planning Project of Guangdong Province,China(2023B1212060050,2023B1212120009)。

摘　　要：Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality.The mechanistic pathophysiology of pancreatitis is complicated,limiting the discovery of pharmacological intervention methods.Here,we show that the administration of ATN-161,an antagonist of Integrin-a5,significantly mitigates the pathological condition of acute pancreatitis induced by caerulein.We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas.In the caerulein-induced acute pancreatitis model,the newly emergent CK19-positive cells are highly vascularized,with a significant increase in vascular density and endothelial cell number.Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners,suggesting the existence of a ductal-endothelial interface in the pancreas.Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/Integrin-a5 signaling.Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia,pathological angiogenesis,and restores other abnormal defects induced by caerulein.Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.

关 键 词：PANCREATITIS ANGIOGENESIS ATN-161 Ductal-endothelial crosstalk Acinar-to-ductal metaplasia 

分 类 号：R576[医药卫生—消化系统]