Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis.
Journal: 2018/December - EMBO Journal
ISSN: 1460-2075
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 we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.
Relations:
Content
Citations
(7)
Genes
(2)
Similar articles
Articles by the same authors
Discussion board
EMBO J 37(7): e98311

Regenerative proliferation of differentiated cells by <span style="fixed-case">mTORC</span>1‐dependent paligenosis

+4 authors

Supporting information

Appendix

Expanded View Figures PDF

Review Process File

Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA,
Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China,
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing, China,
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA,
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA,
Zhen‐Ning Wang, Email: nc.anis@628noeisoj.
Contributor Information.
Corresponding author.
Corresponding author. Tel: +862483283556; E‐mail: nc.anis@628noeisoj,
Corresponding author. Tel: +1 314 362 4213; Fax: +1 314 362 7487; E‐mail: ude.ltsuw@sllimj,
These authors contributed equally to this work
Received 2017 Sep 27; Revised 2018 Jan 18; Accepted 2018 Jan 19.
Click here for additional data file.(970K, pdf)Click here for additional data file.(5.8M, pdf)

Review Process File

Click here for additional data file.(404K, pdf)
Click here for additional data file.(404K, pdf)

Notes

The EMBO Journal (2018) 37: e98311 [Google Scholar]

See also: https://doi.org/10.15252/embj.201899206 (April 2018)

Notes

Contributor Information

Zhen‐Ning Wang, Email: nc.anis@628noeisoj.

Jason C Mills, Email: ude.ltsuw@sllimj.

Contributor Information
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.