Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis

EMBO J. 2018 Apr 3;37(7):e98311. doi: 10.15252/embj.201798311. Epub 2018 Feb 21.


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.

Keywords: dedifferentiation; regeneration; repair; reprogramming; transdifferentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells
  • Animals
  • Autophagosomes / physiology
  • Cell Cycle / physiology
  • Cell Differentiation / physiology*
  • Cell Proliferation / physiology*
  • Cell Transdifferentiation / physiology
  • Cellular Reprogramming / physiology
  • Chief Cells, Gastric / pathology
  • Gastrointestinal Tract / pathology
  • Gene Expression
  • Humans
  • Lysosomes
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Metaplasia / genetics
  • Mice
  • Mice, Inbred C57BL
  • Regeneration / physiology*
  • S Phase / physiology
  • SOX9 Transcription Factor / metabolism
  • Stomach / injuries
  • Stomach / pathology
  • Transferases (Other Substituted Phosphate Groups) / genetics


  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Transferases (Other Substituted Phosphate Groups)
  • GNPTAB protein, mouse