Regenerative proliferation of differentiated cells by mTORC1‐dependent paligenosis. (21st February 2018)

• Record Type: Journal Article
• Authors: Willet, Spencer G; Lewis, Mark A; Miao, Zhi‐Feng; Liu, Dengqun; Radyk, Megan D; Cunningham, Rebecca L; Burclaff, Joseph; Sibbel, Greg; Lo, Hei‐Yong G; Blanc, Valerie; Davidson, Nicholas O; Wang, Zhen‐Ning; Mills, Jason C
• Is Part Of: EMBO journal. Volume 37:Number 7(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-02-21
• Subjects: dedifferentiation -- regeneration -- repair -- reprogramming -- transdifferentiation; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798311
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Upon acute injury, differentiated cells in diverse organs are re‐activated via a common program controlling autodegradative pathways, increased expression of damage‐associated metaplastic genes and cell cycle re‐entry. Differentiated cells in the stomach, pancreas, liver and kidney become proliferative via a shared program, termed here "paligenosis". Metaplasia‐inducing injury caused decreased mTORC1 activity and elevated lysosomes/autophagosomes in both gastric chief and pancreatic acinar cells followed by activation of metaplasia‐associated genes. Blocking mTORC1 permitted autophagy and metaplastic gene induction but impaired subsequent cell cycle re‐entry at S‐phase. Lysosome‐defective Gnptab −/− mice did not exhibit either metaplastic gene expression changes or mTORC1‐mediated proliferation. Abstract : Acute injury elicits proliferation of differentiated cells in diverse organs via a shared program involving upregulation of autodegradative pathways, metaplastic genes and cell cycle re‐entry.