ATN-161 alleviates caerulein-induced pancreatitis

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

doi:10.1016/j.jgg.2024.10.002

ATN-161 alleviates caerulein-induced pancreatitis

doi: 10.1016/j.jgg.2024.10.002

Rong-rong Gao^a,
Lan-yue Ma^b,c,d,
Jian-wei Chen^e,
Yu-xiang Wang^b,c,d,
Yu-yan Li^b,c,d,
Zi-yuan Zhou^f,
Zhao-hua Deng^b,c,d,
Jing Zhong^b,c,d,
Ya-hai Shu^b,d,
Yang Liu^g, ,,
Qi Chen^{a,b,d,e,h, ,}

a. 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;
b. Center for Cell Lineage Atlas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China;
c. University of Chinese Academy of Sciences, Beijing 101408, China;
d. 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;
e. Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, China;
f. 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;
g. The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China;
h. Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China

基金项目:

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)

Cooperation Fund of CHCAMS and SZCH (E010221005, CFA202201006)

National Natural Science Foundation of China (32270866, 32300693, 32471155, 32470868 22107045)

This work is supported by the National Key R&D Program of China (2022YFA1103200)

Talent Program and Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (1103792101, GIBHBRP23-02, GIBHBRP24-01)

South China University of Technology (D6241240)

and partially supported by Science and Technology Planning Project of Guangdong Province, China (2023B1212060050, 2023B1212120009).

The Pearl River Talent Recruitment Program (2023ZT10Y154, 2021ZT09Y233, 2023QN10Y147)

Guangzhou basic and applied basic research funding (2024A04J6259)

the Fundamental Research Funds for the Central Universities (2024ZYGXZR077)

详细信息

通讯作者:
Yang Liu,E-mail:yangl005@scut.edu.cn

Qi Chen,E-mail:chen_qi@gibh.ac.cn

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出版历程
- 收稿日期: 2024-05-27
- 录用日期: 2024-10-03
- 修回日期: 2024-10-02
- 网络出版日期: 2025-06-05
- 刊出日期: 2024-10-11

ATN-161 alleviates caerulein-induced pancreatitis

Rong-rong Gao^a,
Lan-yue Ma^b,c,d,
Jian-wei Chen^e,
Yu-xiang Wang^b,c,d,
Yu-yan Li^b,c,d,
Zi-yuan Zhou^f,
Zhao-hua Deng^b,c,d,
Jing Zhong^b,c,d,
Ya-hai Shu^b,d,
Yang Liu^{g
, ,},
Qi Chen^{a,b,d,e,h
, ,}

a. 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;
b. Center for Cell Lineage Atlas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China;
c. University of Chinese Academy of Sciences, Beijing 101408, China;
d. 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;
e. Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, China;
f. 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;
g. The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China;
h. Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China

Funds:

Cooperation Fund of CHCAMS and SZCH (E010221005, CFA202201006)

National Natural Science Foundation of China (32270866, 32300693, 32471155, 32470868 22107045)

This work is supported by the National Key R&D Program of China (2022YFA1103200)

Talent Program and Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (1103792101, GIBHBRP23-02, GIBHBRP24-01)

South China University of Technology (D6241240)

and partially supported by Science and Technology Planning Project of Guangdong Province, China (2023B1212060050, 2023B1212120009).

The Pearl River Talent Recruitment Program (2023ZT10Y154, 2021ZT09Y233, 2023QN10Y147)

Guangzhou basic and applied basic research funding (2024A04J6259)

the Fundamental Research Funds for the Central Universities (2024ZYGXZR077)

摘要

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-α5, 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-α5 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.
- Pancreatitis /
- Angiogenesis /
- ATN-161 /
- Ductal-endothelial crosstalk /
- Acinar-to-ductal metaplasia
Abstract:
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-α5, 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-α5 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.
- Pancreatitis /
- Angiogenesis /
- ATN-161 /
- Ductal-endothelial crosstalk /
- Acinar-to-ductal metaplasia

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