In vivo partial cellular reprogramming enhances liver plasticity and regeneration.

Publicado en: Nature Communications

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


Hishida T, Yamamoto M, Hishida-Nozaki Y, Shao C, Huang L, Wang C, Shojima K, Xue Y, Hang Y, Shokhirev M, Memczak S, Kumar Sahu S, Hatanaka F, Rabadan Ros R, Maxwell MB, Chavez J, Shao Y, Liao HK, Martinez-Redondo P, Guillen-Guillen I, Hernandez-Benitez R, Rodriguez Esteban C, Qu J, Holmes MC, Yi F, Hickey RD, Guillen Garcia P, Nuñez Delicado E, Castells A, Campistol JM, Yu Y, Hargreaves DC, Asai A, Reddy P, Liu GH, Izpisua Belmonte JC. In vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell Rep. 2022 Apr 26;39(4):110730. doi: 10.1016/j.celrep.2022.110730.


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