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Updated: Jul 11, 2025
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Mfap4: a promising target for enhanced liver regeneration and chronic liver disease treatment
Viktoriia Iakovleva1,2,3, Anna Wuestefeld1, Agnes Bee Leng Ong1
1Laboratory of In Vivo Genetics and Gene Therapy, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore, 138672, Republic of Singapore.
Abstract:
The liver has a remarkable regenerative capacity. Nevertheless, under chronic liver-damaging conditions, this capacity becomes exhausted, allowing the accumulation of fibrotic tissue and leading to end-stage liver disease. Enhancing the endogenous regenerative capacity by targeting regeneration breaks is an innovative therapeutic approach. We set up an in vivo functional genetic screen to identify such regeneration breaks. As the top hit, we identified Microfibril associated protein 4 (Mfap4). Knockdown of Mfap4 in hepatocytes enhances cell proliferation, accelerates liver regeneration, and attenuates chronic liver disease by reducing liver fibrosis. Targeting Mfap4 modulates several liver regeneration-related pathways including mTOR. Our research opens the way to siRNA-based therapeutics to enhance hepatocyte-based liver regeneration.
Insights
Researchers identified Microfibril associated protein 4 (Mfap4) as a key factor limiting liver regeneration. Targeting Mfap4 enhances liver repair and reduces fibrosis, offering a new therapeutic strategy for chronic liver disease.
Area of Science:
- Hepatology and regenerative medicine
- Molecular biology and genetics
Background:
- The liver possesses significant regenerative potential, but chronic damage can exhaust this capacity, leading to fibrosis and end-stage liver disease.
- Current therapeutic strategies for chronic liver disease are limited, highlighting the need for novel approaches to enhance liver repair.
Purpose of the Study:
- To identify genetic factors that limit liver regeneration using an in vivo functional genetic screen.
- To investigate the role of Microfibril associated protein 4 (Mfap4) in liver regeneration and its potential as a therapeutic target.
Main Methods:
- An in vivo functional genetic screen was employed to identify regeneration breaks in the liver.
- The expression and function of Microfibril associated protein 4 (Mfap4) were analyzed in hepatocytes.
- The effects of Mfap4 knockdown on liver regeneration, fibrosis, and related molecular pathways (e.g., mTOR) were assessed.
Main Results:
- Microfibril associated protein 4 (Mfap4) was identified as a top hit in the genetic screen, acting as a brake on liver regeneration.
- Knockdown of Mfap4 in hepatocytes significantly enhanced cell proliferation and accelerated liver regeneration.
- Targeting Mfap4 reduced liver fibrosis in chronic liver disease models and modulated key regeneration pathways like mTOR.
Conclusions:
- Microfibril associated protein 4 (Mfap4) is a critical regulator that inhibits hepatocyte proliferation and liver regeneration.
- Targeting Mfap4 presents a promising therapeutic strategy for enhancing liver regeneration and treating chronic liver disease.
- siRNA-based therapeutics targeting Mfap4 could be developed to promote hepatocyte-based liver regeneration.
