Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis

The EMBO Journal
Spencer G WilletJason C Mills

Abstract

In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9; and finally reactivate mTORC1 and re-enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective Gnptab-/- mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which...Continue Reading

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Citations

Jan 18, 2019·The Journal of Clinical Investigation·Jonathan T BusadaJohn A Cidlowski
Mar 24, 2018·The EMBO Journal·Hendrik A MessalAxel Behrens
Jan 29, 2020·Acta Physiologica·Adrienne M AssmusLinda J Mullins
Apr 8, 2020·ELife·John Me NicholsJonathan R Chubb
Apr 7, 2020·The Journal of Clinical Investigation·José B Sáenz, Jason C Mills
Jun 28, 2018·Digestive Diseases and Sciences·Ramon U Jin, Jason C Mills
May 30, 2020·Cell Biochemistry and Function·Afnan H El-Gowily, Mohammed A Abosheasha
Feb 21, 2019·Cellular and Molecular Life Sciences : CMLS·Alexios-Fotios A MentisAthanasios G Papavassiliou
Jul 25, 2018·Disease Models & Mechanisms·Joseph Burclaff, Jason C Mills
Sep 2, 2018·Disease Models & Mechanisms·Joseph Burclaff, Jason C Mills
Aug 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Xiao-Jun Li, Angelika Doetzlhofer
Aug 7, 2020·American Journal of Physiology. Cell Physiology·Emma TealYana Zavros
Sep 2, 2019·Cellular and Molecular Gastroenterology and Hepatology·Takahiro ShimizuJames R Goldenring
May 10, 2019·Cellular and Molecular Gastroenterology and Hepatology·Anne R MeyerJames R Goldenring
Feb 7, 2021·Development·Lillian B SpatzJason C Mills
Jul 3, 2018·Gastroenterology·Jason C Mills, Linda C Samuelson
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Jul 3, 2021·International Journal of Molecular Sciences·Shaida Ouladan, Alex Gregorieff
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Aug 6, 2021·Cellular and Molecular Gastroenterology and Hepatology·Adrien GrimontRohit Chandwani
Aug 30, 2021·Cellular and Molecular Gastroenterology and Hepatology·Su-Hyung LeeJames R Goldenring
Sep 22, 2021·Cellular and Molecular Gastroenterology and Hepatology·Min-Jiao PangZhen-Ning Wang
Aug 7, 2021·Cellular and Molecular Gastroenterology and Hepatology·Jonathan T BusadaPerry J Blackshear
Nov 4, 2021·Communications Biology·Miriam Jacome-SosaNada A Abumrad
Oct 28, 2020·Developmental Cell·Nicolette M Johnson, Christopher J Lengner
Jul 13, 2019·Science·Thea D Tlsty, Philippe Gascard
Oct 26, 2021·Gastroenterology·Zhibo MaKathleen E DelGiorno
Nov 4, 2021·Gastroenterology·James R Goldenring, Jason C Mills

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