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-Guillen; Reyna 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

doi:10.1016/j.celrep.2022.110730

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

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Research output: Contribution to journal › Article › peer-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 language	English (US)
Article number	110730
Journal	Cell reports
Volume	39
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2022.110730
State	Published - Apr 26 2022

Keywords

CP: Stem cell research
dedifferentiation
liver
regeneration
reprogramming

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110730

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Hishida, T., Yamamoto, M., Hishida-Nozaki, Y., Shao, C., Huang, L., Wang, C., Shojima, K., Xue, Y., Hang, Y., Shokhirev, M., Memczak, S., Sahu, S. K., Hatanaka, F., Ros, R. R., Maxwell, M. B., Chavez, J., Shao, Y., Liao, H. K., Martinez-Redondo, P., ... Izpisua Belmonte, J. C. (2022). In vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell reports, 39(4), Article 110730. https://doi.org/10.1016/j.celrep.2022.110730

Hishida, T, Yamamoto, M, Hishida-Nozaki, Y, Shao, C, Huang, L, Wang, C, Shojima, K, Xue, Y, Hang, Y, Shokhirev, M, Memczak, S, Sahu, SK, Hatanaka, F, Ros, RR, Maxwell, MB, Chavez, J, Shao, Y, Liao, HK, Martinez-Redondo, P, Guillen-Guillen, I, Hernandez-Benitez, R, Esteban, CR, Qu, J, Holmes, MC, Yi, F, Hickey, RD, Garcia, PG, Delicado, EN, Castells, A, Campistol, JM, Yu, Y, Hargreaves, DC, Asai, A, Reddy, P, Liu, GH & Izpisua Belmonte, JC 2022, 'In vivo partial cellular reprogramming enhances liver plasticity and regeneration', Cell reports, vol. 39, no. 4, 110730. https://doi.org/10.1016/j.celrep.2022.110730

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title = "In vivo partial cellular reprogramming enhances liver plasticity and regeneration",

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.",

keywords = "CP: Stem cell research, dedifferentiation, liver, regeneration, reprogramming",

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

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

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day = "26",

doi = "10.1016/j.celrep.2022.110730",

language = "English (US)",

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T1 - In vivo partial cellular reprogramming enhances liver plasticity and regeneration

AU - Hishida, Tomoaki

AU - Yamamoto, Mako

AU - Hishida-Nozaki, Yuriko

AU - Shao, Changwei

AU - Huang, Ling

AU - Wang, Chao

AU - Shojima, Kensaku

AU - Xue, Yuan

AU - Hang, Yuqing

AU - Shokhirev, Maxim

AU - Memczak, Sebastian

AU - Sahu, Sanjeeb Kumar

AU - Hatanaka, Fumiyuki

AU - Ros, Ruben Rabadan

AU - Maxwell, Matthew B.

AU - Chavez, Jasmine

AU - Shao, Yanjiao

AU - Liao, Hsin Kai

AU - Martinez-Redondo, Paloma

AU - Guillen-Guillen, Isabel

AU - Hernandez-Benitez, Reyna

AU - Esteban, Concepcion Rodriguez

AU - Qu, Jing

AU - Holmes, Michael C.

AU - Yi, Fei

AU - Hickey, Raymond D.

AU - Garcia, Pedro Guillen

AU - Delicado, Estrella Nuñez

AU - Castells, Antoni

AU - Campistol, Josep M.

AU - Yu, Yang

AU - Hargreaves, Diana C.

AU - Asai, Akihiro

AU - Reddy, Pradeep

AU - Liu, Guang Hui

AU - Izpisua Belmonte, Juan Carlos

PY - 2022/4/26

Y1 - 2022/4/26

N2 - 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.

AB - 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.

KW - CP: Stem cell research

KW - dedifferentiation

KW - liver

KW - regeneration

KW - reprogramming

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DO - 10.1016/j.celrep.2022.110730

M3 - Article

C2 - 35476977

AN - SCOPUS:85128971770

SN - 2211-1247

VL - 39

JO - Cell reports

JF - Cell reports

IS - 4

M1 - 110730

ER -

In vivo partial cellular reprogramming enhances liver plasticity and regeneration

Abstract

Keywords

ASJC Scopus subject areas

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