학술논문
In vivopartial cellular reprogramming enhances liver plasticity and regeneration
Document Type
Article
Author
Hishida, Tomoaki; Yamamoto, Mako; Hishida-Nozaki, Yuriko; Shao, Changwei; Huang, Ling; Wang, Chao; Shojima, Kensaku; Xue, Yuan; Hang, Yuqing; Shokhirev, Maxim; Memczak, Sebastian; Sahu, Sanjeeb Kumar; Hatanaka, Fumiyuki; Ros, Ruben Rabadan; Maxwell, Matthew B.; Chavez, Jasmine; Shao, Yanjiao; Liao, Hsin-Kai; Martinez-Redondo, Paloma; Guillen-Guillen, Isabel; Hernandez-Benitez, Reyna; Esteban, Concepcion Rodriguez; Qu, Jing; Holmes, Michael C.; Yi, Fei; Hickey, Raymond D.; Garcia, Pedro Guillen; Delicado, Estrella Nuñez; Castells, Antoni; Campistol, Josep M.; Yu, Yang; Hargreaves, Diana C.; Asai, Akihiro; Reddy, Pradeep; Liu, Guang-Hui; Izpisua Belmonte, Juan Carlos
Source
Cell Reports; April 2022, Vol. 39 Issue: 4
Subject
Language
ISSN
22111247
Abstract
Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivoinduces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration.