Regulation of liver regeneration by microRNAs
Final Report Abstract
The aim of the project was to identify and investigate regulators of liver regeneration, especially those, which regulate the termination phase of liver regeneration. Based on microRNA profiling and subsequent functional validation, we identified miR-125b-5p as an important regulator of liver regeneration. We found that the expression of miR-125b-5p decreases during the termination phase of liver regeneration. Our in vivo studies demonstrated that hepatocyte-specific overexpression of miR-125b-5p enhances proliferation of hepatocytes. Mechanistically, we discovered that miR-125b-5p binds to the 3’UTR of Abtb1, which encodes for ABTB1 protein that has an ankyrin repeats region and two BTB/POZ domains. In concert with our in vitro results, we found that Abtb1 was consistently downregulated (<2-fold) in mice treated with AAV8-Ttr-miR-125b-5p. The siRNA-mediated loss of ABTB1 phenocopied the effects what were observed upon gain of miR-125b-5p. Furthermore, we demonstrated that miR- 125b-5p promotes proliferation of primary human hepatocytes via post-transcriptional regulation of ABTB1. The results of this project uncover a novel regulation of termination of liver regeneration. Our findings suggest that miR-125b-5p may serve as an enhancer of hepatocytes proliferation, and hence can be used to overcome impaired liver regeneration, which are often seen during endstage liver diseases. This is supported by the observation that miR-125b-5p overexpression is able to suppress acute liver failure in mouse models. Additionally, due to the fact that a single microRNA is able to regulate the expression of multiple genes and transcription factors, in vivo reprogramming of hepatic cells induced either by microRNAs or transcription factors can be utilized a potential approach for the attenuation of chronic liver injuries such as fibrosis. Our recent reports provide evidence that in vivo modulation of microRNAs such as miR-221-3p or transcription factors-induced reprogramming are plausible approaches to suppress liver fibrosis. In addition to treating acute liver failure, it remains to be seen whether molecules that regulate termination of liver regeneration can also affect uncontrolled proliferation, which is one of the hallmarks of liver cancer. Therefore, it is imperative to investigate the effect of in vivo modulation of regulators identified from this study in various models of liver cancer, wherein hepatocyte proliferation and resistance to cell death are key drivers of tumor progression.
Publications
- Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis. Cell Stem Cell 2016, 18:797-808 [“Publication of the Year Award” by German Stem Cell Network (GSCN) and German association of the study of the liver (GASL) prize]
Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, Reetz J, Brandes S, Dai Z, Putzer BM, Arauzo-Bravo MJ, Steinemann D, Luedde T, Schwabe RF, Manns MP, Scholer HR, Schambach A, Cantz T, Ott M, Sharma AD
(See online at https://doi.org/10.1016/j.stem.2016.01.010) - MicroRNA-125b-5p mimic inhibits acute liver failure. Nat Commun 2016, 7:11916
Yang D, Yuan Q, Balakrishnan A, Bantel H, Klusmann JH, Manns MP, Ott M, Cantz T, Sharma AD
(See online at https://doi.org/10.1038/ncomms11916) - Hepatocytespecific suppression of microRNA-221-3p mitigates liver fibrosis. J Hepatol 2019, 70:722-34
Tsay HC, Yuan Q, Balakrishnan A, Kaiser M, Mobus S, Kozdrowska E, Farid M, Tegtmeyer PK, Borst K, Vondran FWR, Kalinke U, Kispert A, Manns MP, Ott M, Sharma AD
(See online at https://doi.org/10.1016/j.jhep.2018.12.016)
