Cholangiocyte-derived exosomal long noncoding RNA PICALM-AU1 promotes pulmonary endothelial cell endothelial-mesenchymal transition in hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is a severe lung injury caused by chronic liver disease, with limited understanding of the disease pathology. Exosomes are important mediators of intercellular communication that modulates various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies have indicated that a new long noncoding RNA (lncRNA), PICALM-AU1, is mainly expressed in cholangiocytes, and is dramatically induced in the liver during HPS. However, the mechanism by which cholangiocyte-derived PICALM-AU1 regulates Endothelial-mesenchymal transition (EndMT) in HPS remains unclear. Here, we observed that PICALM-AU1 was synthesized in the cholangiocytes of the liver and then, secreted as exosomes into the serum; serum exosomal PICALM-AU1 levels were positively correlated with the severity of HPS in a rat model and in human patients. PICALM-AU1 carrying serum exosomes induced the EndMT of pulmonary microvascular endothelial cells (PMVECs) and promoted lung injury in vivo and in vitro. Furthermore, PICALM-AU1 acted as a molecular sponge for microRNA 144-3p (miR144-3p), resulting in the up-regulation of Zinc Finger E-Box Binding Homeobox 1 (ZEB1), a known target of EndMT and enhancement of EndMT, proliferation and migration of PMVECs. Taken together, our findings indicate that the cholangiocyte-derived exosomal lncRNA PICALM-AU1 plays a critical role in the EndMT in HPS lungs. Thus, it represents a potential therapeutic target for the treatment of HPS.