June 22, 2023

Pathways to a healthy liver

Hepatic stellate cells maintain liver mass and function; the signaling factors they use could be exploited therapeutically to promote liver regeneration and inhibit cancerous proliferation, Vanderbilt researchers suggest.

When activated by liver injury, hepatic stellate cells (HSCs) promote repair and regeneration, but also drive the development of scar tissue and cancer. Understanding how these cells function is crucial to improving the treatment of liver diseases including cirrhosis. 

To explore the role that HSCs play in their quiescent state in the healthy liver, Youngmin Lee, MD, PhD, and colleagues used immune cells to ablate, or eliminate, nearly all HSCs in a mouse model. 

Ablation caused the liver to shrink because CCND1-positive hepatocytes, liver cells that normally preserve liver mass, stopped proliferating. Levels of neurotrophin-3 (NTF3), a protein produced by HSCs, also declined. 

When added to depleted livers in vitro, NTF3 increased CCND1 expression and drove hepatocyte proliferation by stimulating the receptor TrkB. 

These findings, reported May 30 in the journal Science Signaling, demonstrate the importance of HSCs in maintaining liver mass and function, and suggest that these pathways could be exploited therapeutically to promote liver regeneration and inhibit cancerous proliferation.

Vanderbilt University Medical Center’s Vincent Quoc-Huy Trinh, MD, and Ting-Fang Lee, PhD, are co-first authors of the paper, which was co-written by colleagues from the Icahn School of Medicine in New York and Harvard Medical School. Others from VUMC who contributed were Kevin Ray and Kemal Akat, MD, PhD.

The research was supported in part by National Institutes of Health grants DK058404, DK058404, CA236733, DK056621, DK128289, and AT011326, and the American Cancer Society.