A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle

Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term “paligenosis” to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1^−/− cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4^−/− cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. Video Abstract: [Figure presented] During regeneration or tumorigenesis, differentiated cells use an evolutionarily conserved program (paligenosis) to reprogram their metabolism and readopt a progenitor state. Miao et al. identify dedicated paligenosis genes: DDIT4 suppresses mTORC1 to induce massive autophagy that dismantles differentiated cell architecture, then IFRD1 derepresses mTORC1, licensing the dedifferentiated cell to proliferate.