Int J Biol Sci 2021; 17(3):861-868. doi:10.7150/ijbs.56091

Research Paper

PTEN-mediated AKT/β-catenin signaling enhances the proliferation and expansion of Lgr5+ hepatocytes

Jimin Han1,2,3*, Kaijun Lin3*, Xuezheng Zhang3*, Lingchen Yan3*, Yu Chen1,2,3*, Haiyan Chen1,2,3*, Jianjun Liu4, Jia Liu3✉, Yaojiong Wu1,2✉

1. School of Life Sciences, Tsinghua University, China.
2. The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, China.
3. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China.
4. Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, 518054, Shenzhen, China.
* These six are the first authors of this manuscript.

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Citation:
Han J, Lin K, Zhang X, Yan L, Chen Y, Chen H, Liu J, Liu J, Wu Y. PTEN-mediated AKT/β-catenin signaling enhances the proliferation and expansion of Lgr5+ hepatocytes. Int J Biol Sci 2021; 17(3):861-868. doi:10.7150/ijbs.56091. Available from https://www.ijbs.com/v17p0861.htm

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Abstract

Rationale: Compelling evidence suggests that Lgr5+ hepatocytes repair liver damage by promoting the regeneration of hepatocytes and ductal cells in the case of liver injury. The PTEN-mediated AKT/β-catenin signaling plays a key role in the regulation of innate immune regulation in the liver. However, the signaling pathways that control Lgr5+ hepatocyte proliferation in the liver remain unclear.

Methods: In order to assess the involvement of PTEN-mediated AKT/β-catenin signaling in the expansion of Lgr5+ hepatocytes upon liver injuries, the Lgr5-CreER; Rosa-mTmG lineage tracing system was used to target Lgr5+ hepatocytes.

Results: The tracing of Lgr5+ hepatocytes showed that PTEN deletion and β-catenin activation significantly promoted the proliferation of Lgr5+ hepatocytes. In converse, the simultaneous inhibition of PTEN and β-catenin limited Lgr5+ hepatocyte proliferation in the liver. Our findings provide an insight into understanding how PTEN-mediated AKT/β-catenin signaling regulates the proliferation of Lgr5+ hepatocytes.

Conclusion: The outcomes can improve the application potential of Lgr5+ hepatocytes in the treatment of liver injury diseases and provide a new treatment option for liver cancer.

Keywords: AKT/β-catenin, Lgr5, hepatocyte, proliferation, liver regeneration.