Iakovleva Viktoriia, Wuestefeld Anna, Ong Agnes Bee Leng, Gao Rong, Kaya Neslihan Arife, Lee May Yin, Zhai Weiwei, Tam Wai Leong, Dan Yock Young, Wuestefeld Torsten
Laboratory 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.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Republic of Singapore.
NPJ Regen Med. 2023 Nov 7;8(1):63. doi: 10.1038/s41536-023-00337-9.
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.
肝脏具有显著的再生能力。然而，在慢性肝损伤条件下，这种能力会耗尽，从而使纤维化组织积累并导致终末期肝病。通过靶向再生断点来增强内源性再生能力是一种创新的治疗方法。我们建立了一个体内功能基因筛选来识别此类再生断点。作为最显著的发现，我们鉴定出微原纤维相关蛋白4（Mfap4）。在肝细胞中敲低Mfap4可增强细胞增殖、加速肝脏再生，并通过减少肝纤维化来减轻慢性肝病。靶向Mfap4可调节包括mTOR在内的几种肝脏再生相关途径。我们的研究为基于siRNA的疗法开辟了道路，以增强基于肝细胞的肝脏再生。
