Lipopolysaccharide induces the differentiation of hepatic progenitor cells into myofibroblasts via activation of the Hedgehog signaling pathway

Abstract

Normally, hepatic progenitor cells (HPCs) are activated and differentiate into hepatocytes or bile ductular cells to repair liver damage during liver injury. However, it remains controversial whether the abnormal differentiation of HPCs occurs under abnormal conditions. Lipopolysaccharide (LPS), a component of the microenvironment, promotes liver fibrosis. In the present study, HPCs promoted liver fibrosis in rats following carbon tetrachloride (CCl₄) treatment. Meanwhile, the LPS level in the portal vein was elevated and played a primary role in the fate of HPCs. In vitro, LPS inhibited the hepatobiliary differentiation of HPCs. Concurrently, HPCs co-cultured with LPS for 2 weeks showed a tendency to differentiate into myofibroblasts (MFs). Thus, we conclude that LPS promotes the aberrant differentiation of HPCs into MFs as a third type of descendant. This study provides insight into a novel differentiation fate of HPCs in their microenvironment, and could thus lead to the development of HPCs for treatment methods in liver fibrosis.

KEYWORDS:

• differentiation
• hepatic progenitor cells
• liver fibrosis
• lipopolysaccharide
• myofibroblasts

Ethics approval

Experiments and all procedures involving animals were performed in accordance with the institutional animal welfare guidelines of Second Military Medical University and approved by the Animal Ethics Committee of Eastern Hepatobiliary Surgery Hospital, Shanghai, China.

Disclosure of potential conflicts of interest

The authors declare that they have no competing interests

Funding

This project was supported by National Natural Science Foundation of China (Grant No. 81401308, 81402026, 81402454, 81402018, 81402020, 81630070, 81372312, 81472737, 81572444, 81502417); Special Funds for National Key Sci-Tech Sepcial Project of China (Grant No. 2016ZX10002019-005-002); Shanghai Science and Technology Committee (Grant No. 15PJ1410600, 14ZR1409200, 16ZR1400200, 16JC1405200, 14ZD1900403, 16YF1415000); Science Fund for Creative Research Groups, NSFC, China (Grant NO. 81521091).

Author's Contribution

Xiaorong Pan, Yingying Jing and Wenting Liu performed the research, analyzed data, and participated in writing the paper. Zhipeng Han, Jingni Zhu, Xiaoyong Li and Peipei Li analyzed data and composed this paper. Yang Yang and Rong Li participated in performing this study. Lixin Wei conceived this study, provided funding, and gave final approval of this paper.