The role of TGF-beta signaling in liver progenitor cell proliferation and differentiation

• Applicant: Honglei Weng, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574711027

Liver progenitor cells (LPCs) are liver specific stem-cell like population that mediate the second pathway of liver regeneration in severe disease such as acute liver failure (ALF). The mechanisms how LPCs remain quiescent, but rapidly proliferate, perform hepatic function, and subsequently differentiate into hepatocytes when required are largely unknown. Inflammatory mediators are commonly considered to control LPC activation. In the last funding phase, we clarified how inflammatory and metabolic regulators such as activin, TGF-beta, FOXO2, and glucagon combine to determine the fate of LPC under duress and thus the survival of seriously ill patients. In the next phase, we plan to dive deeper in the molecular mechanisms of how TGF-beta family members and their downstream transcription factors in the regulation of LPC proliferation and differentiation. Here we propose the following hypotheses to explain the role of the TGF-beta-SMAD signaling in LPC regulation: (1) Physiologically, TGF-beta-SMAD signaling maintains LPC in a quiescent state. (2) Following liver damage, proliferation of LPC is induced when external inflammatory mediators override TGF-beta-SMAD signaling. (3) TGF-beta-SMAD signaling inhibits LPC-to-hepatocyte differentiation, although it is essential to induce vital hepatic genes in LPCs. To test these hypotheses, specific cell context such as epigenetic landscape in both LPCs and hepatocytes, which determines the TGF-beta-SMAD signaling response, will be examined in cultured cells and liver tissues collected from ALF patients through multiple bioinformatic analyses. The role and potential mechanisms of the TGF-beta-SMAD signaling in LPC proliferation and differentiation will be investigated in cultured LPCs, 3,5-Diethoxycarbonyl-1,4-dihydrocollidin-fed mice and metronidazole-treated zebrafish. Clarification of the exact molecular mechanisms of how TGF-beta-SMAD signaling regulate LPC proliferation and differentiation will enhance our understanding of LPC biology and provide novel targets for therapeutic intervention in ALF.

• DFG Programme: Research Grants