Targeting ductal-endothelial crosstalk alleviate pancreatitis

Abstract

Pancreatitis are common gastrointestinal disorders that cause hospitalization with significant morbidity and mortality. The mechanistic pathophysiology of pancreatitis is complicated, which greatly limits the discovery of pharmacological intervention methods. Here, we show that administration of antagonist of Integrin-α5, significantly mitigates the pathological condition of acute pancreatitis. In caerulein-induced acute pancreatitis model, the newly emergent CK19 positive cells are highly vascularized with significant increase of vascular density and endothelial cell number. Single cell RNA sequencing analysis shows ductal and endothelial cells are intimate interacting partners. Pancreatitis dramatically reduce the crosstalk in ductal-endothelial interface but promote the integrin-α5 signaling. Blocking this signaling significantly reduce acinar-to-ductal metaplasia, pathological angiogenesis and restore other abnormal defects induced by caerulein. Our work reveals a therapeutic potential of targeting Integrin-α5 as uncharacterized pharmacological method to alleviate the symptom of pancreatitis.