In vivo partial cellular reprogramming enhances liver plasticity and regeneration

Tomoaki Hishida, Mako Yamamoto, Yuriko Hishida-Nozaki, Changwei Shao, Ling Huang, Chao Wang, Kensaku Shojima, Yuan Xue, Yuqing Hang, Maxim Shokhirev, Sebastian Memczak, Sanjeeb Kumar Sahu, Fumiyuki Hatanaka, Ruben Rabadan Ros, Matthew B. Maxwell, Jasmine Chavez, Yanjiao Shao, Hsin Kai Liao, Paloma Martinez-Redondo, Isabel Guillen-GuillenReyna Hernandez-Benitez, Concepcion Rodriguez Esteban, Jing Qu, Michael C. Holmes, Fei Yi, Raymond D. Hickey, Pedro Guillen Garcia, Estrella Nuñez Delicado, Antoni Castells, Josep M. Campistol, Yang Yu, Diana C. Hargreaves, Akihiro Asai, Pradeep Reddy, Guang Hui Liu, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticlepeer-review

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 vivo 4F 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 vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration.

Original languageEnglish (US)
Article number110730
JournalCell reports
Volume39
Issue number4
DOIs
StatePublished - Apr 26 2022

Keywords

  • CP: Stem cell research
  • dedifferentiation
  • liver
  • regeneration
  • reprogramming

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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