Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

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 ; 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 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.

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

“…Cellular plasticity is induced in several tissues as part of the normal injury response (Merrell and Stanger, 2016; Tata and Rajagopal, 2016). Our data suggest that Mist1 + acinar cells also undergo cell type transitions in irradiated glands, consistent with reports documenting the plasticity of other differentiated secretory cells (Willet et al, 2018; Yu et al, 2018). This suggests that several cell populations have regenerative potential useful for restoring salivary gland function.…”

β-catenin Signaling Regulates Cell Fate Decisions at the Transition Zone of the Chondro-Osseous Junction During Fracture Healing

“…Recently, Willet et al coined the term "paligenosis" to describe the process by which differentiated cells revert to a proliferative and regenerative state and undergo metaplasia in response to tissue injury in the context of stomach and pancreatic regeneration. 42 Our data suggest a similar process occurs in the context of fracture repair.…”

Pyloric metaplasia, pseudopyloric metaplasia, ulcer‐associated cell lineage and spasmolytic polypeptide‐expressing metaplasia: reparative lineages in the gastrointestinal mucosa

“…While one group has suggested that SPEM arises from isthmal progenitor cells in the corpus [57], the vast majority of evidence from multiple groups indicates that chief cells are indeed the predominant origin of SPEM lineages in the stomach corpus. [42,47,56,58–60] Importantly, expression of pepsinogen I has been used as a marker of pseudopyloric metaplasia [61], consistent with the equivalence of pseudopyloric metaplasia with SPEM. Similarly, ductal metaplasia/PanIN lesions in the pancreas appear to evolve from reprogramming of zymogen-secreting pancreatic acinar cells [62].…”

“…SPEM appears to arise in the setting of parietal cell loss or acute corpus mucosal damage, primarily through transdifferentiation of chief cells into mucous cell metaplasia [42,47,56]. While one group has suggested that SPEM arises from isthmal progenitor cells in the corpus [57], the vast majority of evidence from multiple groups indicates that chief cells are indeed the predominant origin of SPEM lineages in the stomach corpus [42,47,56,[58][59][60]. Importantly, expression of pepsinogen I has been used as a marker of pseudopyloric metaplasia [61], consistent with the equivalence of pseudopyloric metaplasia with SPEM.…”