2. Academic Validation
  3. ATN-161 alleviates caerulein-induced pancreatitis

ATN-161 alleviates caerulein-induced pancreatitis

  • J Genet Genomics. 2024 Oct 11:S1673-8527(24)00262-5. doi: 10.1016/j.jgg.2024.10.002.
Rong-Rong Gao 1,  Lan-Yue Ma 2,  Jian-Wei Chen 3,  Yu-Xiang Wang 2,  Yu-Yan Li 2,  Zi-Yuan Zhou 4,  Zhao-Hua Deng 2,  Jing Zhong 2,  Ya-Hai Shu 5,  Yang Liu 6,  Qi Chen 7
Affiliations

Affiliations

  • 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; University of Chinese Academy of Sciences, Beijing 101408, China; 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.
  • 3 Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, China.
  • 4 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.
  • 5 Center for Cell Lineage Atlas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; 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.
  • 6 The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China. Electronic address: yangl005@scut.edu.cn.
  • 7 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; Center for Cell Lineage Atlas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; 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; Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, China; Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: chen_qi@gibh.ac.cn.
PMID: 39396744 DOI: 10.1016/j.jgg.2024.10.002
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.

Keywords

ATN-161; Acinar-to-ductal metaplasia; Angiogenesis; Ductal-endothelial crosstalk; Pancreatitis.

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