Paligenosis: Cellular Remodeling During Tissue Repair

Abstract

Complex multicellular organisms have evolved specific mechanisms to replenish cells in homeostasis and during repair. Here, we discuss how emerging technologies (e.g., single-cell RNA sequencing) challenge the concept that tissue renewal is fueled by unidirectional differentiation from a resident stem cell. We now understand that cell plasticity, i.e., cells adaptively changing differentiation state or identity, is a central tissue renewal mechanism. For example, mature cells can access an evolutionarily conserved program (paligenosis) to reenter the cell cycle and regenerate damaged tissue. Most tissues lack dedicated stem cells and rely on plasticity to regenerate lost cells. Plasticity benefits multicellular organisms, yet it also carries risks. For one, when long-lived cells undergo paligenotic, cyclical proliferation and redifferentiation, they can accumulate and propagate acquired mutations that activate oncogenes and increase the potential for developing cancer. Lastly, we propose a new framework for classifying patterns of cell proliferation in homeostasis and regeneration, with stem cells representing just one of the diverse methods that adult tissues employ. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Single-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis

“…Recently a conserved program for cellular plasticity in epithelial cells was defined, termed paligenosis. Paligenosis occurs via 3 stages: Stage1, massive activation of autophagy and lysosomal activity as mTORC1 is extinguished; Stage2, re-expression of progenitor or embryonic markers without mTORC1 expression; Stage3, induction of high mTORC1 with cell cycle entry 19 , 20 , 74 – 77 , consistent with a previous study 78 . Previously, paligenosis has been shown as the process differentiated cells use to return to the progenitor state in precancerous states like gastric metaplasia.…”

“…Paligenosis was originally defined as the program by which differentiated (mitotically quiescent) cells use autophagy and dynamic mTORC1 regulation to reprogram into dividing cells in precancerous lesions like metaplasia 19 . This process has been proposed that if GC arises from metaplasia that arose via paligenosis, then perhaps GC cells may use paligenosis to survive 20 . Accordingly, we show here that two autophagy-related genes ( MARCKS and TXNIP ) were identified as biomarkers of high-plasticity GC.…”

A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair

“…The concept gained popularity in the 1800s, was based on histological and anatomical observations, and is often discussed in terms of pathological changes in tissue in response to environmental insult such as with Barrett’s esophagus (Zhang et al 2021) or in the context of cancer as reviewed (Giroux and Rustgi 2017). However, recent evidence suggests that metaplasia and cellular plasticity contribute to development and regeneration within the musculoskeletal system and beyond (Kaji et al 2020; Brown et al 2022; Goldenring and Mills 2022). Metaplasia appears to be common in normal and pathologic processes in multicellular organisms.…”

Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research

“…There are three different sets of antithetical cellular properties that pertain to the obstruction of maturation (Table 1). First, a normal cell can be well-differentiated but still possesses a strong proliferation potential [646,647], evincing that differentiation and proliferation are not incompatible [44,149,415], although cells that proliferate robustly are usually less differentiated. As noted by Harris [415,648], it has become an "ancient question of whether a tumor grows rapidly because it does not differentiate or does not differentiate because it grows rapidly, but this is a false question."…”