YAP affects the efficacy of liver progenitor cells transplantation in CCl4-induced acute liver injury

Abstract

The liver is a highly regenerative organ. During acute liver injury, the remaining hepatocytes rapidly proliferate to restore liver parenchyma and liver function. However, hepatocytes-driven regeneration is compromised in severe liver injury; instead, liver progenitor cells (LPCs) proliferate and differentiate into hepatocytes or cholangiocytes to restore mass and function of liver. The Hippo signaling pathway is of vital importance in liver regeneration, and Yes-associated protein (YAP) is the key component of the Hippo pathway. The therapeutic role of YAP has been well studied in hepatocytes-driven liver regeneration. However, the role of LPCs transplantation in acute liver injury has not been defined. Here, we investigated the therapeutic effect of splenic-transplantation of LPCs in CCl4-induced acute liver injury and explored the role of YAP during the procedure. LPCs isolated from choline-deficient, ethionine-supplemented diet (CDE) model were infected with GFP-YAP cDNA lentiviral vector, GFP-YAP shRNA lentiviral vector, and GFP lentiviral vector as control, respectively. At 48 h after CCl4 injection, PBS (control group), GFP lentiviral vector-infected LPCs (GFP-LPC group), GFP-YAP cDNA lentiviral vector-infected LPCs (YAP-LPC group) and GFP-YAP shRNA lentiviral vector-infected LPCs (sh-YAP-LPC group) were injected into spleens in CCl4-treated mice. Histological and serological analyses were performed to evaluate pathology and liver function. The effect of LPCs on the proliferation of hepatocytes and inflammation was investigated. We demonstrated that intra-splenic transplantation of LPCs alleviates CCl4-induced acute liver injury and YAP signaling acts a key role during the procedure. Further studies suggested that LPCs alleviate acute liver injury by promoting pre-existing hepatocytes proliferation rather than differentiating into hepatocytes. Furthermore, intra-splenic transplantation of LPCs attenuates inflammation, which facilitates tissue repair in acute liver injury. In conclusion, LPCs transplantation is a potential treatment for acute liver injury and YAP is a prospective therapeutic target in acute liver injury.