Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis.
EMBO J
; 37(7)2018 04 03.
Article
em En
| MEDLINE
| ID: mdl-29467218
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.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Regeneração
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Diferenciação Celular
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Proliferação de Células
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Alvo Mecanístico do Complexo 1 de Rapamicina
Limite:
Animals
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Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos