Biology:Paligenosis

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Short description: Cell renewal process for injured tissue

Paligenosis (/pɑːliːdʒɛnoʊsɪs/) is a cellular program in which mature, quiescent, cells revert to a stem cell-like progenitor state in response to injury as a means to restore tissue damage. In 2018, paligenosis was first formally named and described as a three-stage series of defined molecular and cellular events that appear to be conserved across tissue types and throughout biology.[1][2] As such, it is considered a fundamental cellular process akin to apoptosis, mitosis, and other cellular programs.

History and etymology

Cellular plasticity and regeneration have long been observed in the animal kingdom, with examples such as regeneration of lizard's tail[3] or salamander's limb[4] found in scientific literature dating back to the 18th century. The concept of metaplasia was introduced in 1886 to describe a mode of cell plasticity in which cells of a lesion acquire an identity that is unusual within a given tissue while that tissue retains its normal features.[5] In the 20th century, further investigation detailed examples of regeneration in various organs or species, including amphibian eggs.[6][7][8][9][10][11][12][13][14] Much of this early work on regeneration was primarily focused on unidirectional, forward, mitotic processes. However, in 1900, pathologist John George Adami observed that differentiated cells are also able to revert to a pre-mitotic and regenerative state upon injury and speculated that this process is governed by a sequence of energetic and structural changes in the cell.[15] A more detailed understanding of these changes and related mechanisms did not come until early in the 21st century with the advent of genetic tools and approaches. In 2006, researchers identified some of the first key molecular factors that induce differentiated cells to become reprogrammed as pluripotent stem cells.[16] Other biomarkers similarly indicative of reversion to a stem cell-like state were reported in the following years.[17][18][19] And in 2018, a three-stage series of metabolic changes that govern the cellular shift to a pre-mitotic state and subsequent re-entry into the cell cycle was characterized using the mouse stomach and pancreas as models, but also showing evidence of analogous processes in other organs and in humans.[1] Pathologist Jason Mills and colleagues named this cellular program paligenosis, which was derived from the Greek pali/n/m (meaning backward or recurrence) + genea (born of, producing) + osis (an action or process).[1][20][21]

Description

Illustration of the three stages of paligenosis. In the first stage, mTORC1 levels decrease as authophagy and lysosome activity inititates autodegradation of cellular components. In the second stage, metaplasia and progenitor gene expression is initiated. In the third stage, mTORC1 levels and autophagy activity returns to normal as cells re-enter the cell cycle and proliferate. This path results in dedifferentiated cells in a metaplastic state, or redifferentiated cells returning to homeostasis.
Illustration of the three stages of paligenosis.

Paligenosis is defined by three distinct stages of metabolic changes with intervening checkpoints. This stepwise process is governed by specific molecular factors, which are conserved across organs and species.

Stage 1: Autodegradation

The first stage of paligenosis is initiated by an injury-induced suppression of mTORC1,[22] a regulatory protein complex that activates the translation of proteins. Meanwhile, autophagy and lysosome activity begins to increase, enabling cellular components to be degraded and repurposed. The suppression of mTORC1 is regulated by the DDIT4 protein in healthy cells, making it a gatekeeper and key factor for initiating and regulating this stage.[23][24] The increase in autophagy activity is regulated by increased expression of ATF3 protein upon injury and consequential induction of the lysosomal trafficking RAB7B protein.[25]

Stage 2: Metaplastic Gene Expression

As autodegradation activity reaches its peak, expression levels increase for a pair of metaplasia-associated genes, Sox9 and Cd44v.[26] mTORC1 activity begins increasing as lysosome and autophagy activity declines. During this stage, mTORC1 is initially suppressed by the protein p53 (also known as TRP53), but healthy cells are able to accumulate IFRD1 protein that eventually facilitates p53 suppression, allowing mTORC1 levels to rise again.[23][24] The modulation of mTORC1 and autophagy in the first two stages thus serves as checkpoints that allow only healthy cells to proliferate.[27]

Stage 3: Cell Cycle Re-entry

In the final stage, mTORC1 activity continues to increase, while lysosome and autophagy activities return to baseline levels. This allows the cell to enter into a proliferative state as it returns to the cell cycle.

Paligenosis is linked to other cellular processes, and research has investigated its role in ribosome biogenesis,[28] the Hippo pathway,[29] and a reactive oxygen species pathway.[30]

Ubiquity in biology

Accumulating evidence suggests that the steps of paligenosis are evolutionarily conserved across species and different tissues, indicating that paligenosis is a fundamental biological process.[31] Paligenosis has been studied most extensively in the mouse stomach, where it is often induced by Heliobacter pylori bacterial infection and marked by the loss of gastric parietal cells and reversion of chief cells to an embryonic-like progenitor state.[32][33] This condition, referred to as atrophic gastritis, is a type of metaplasia known as pseudopyloric or pyloric metaplasia. At the base of pyloric metaplasia, lesions are composed of spasmolytic polypeptide-expressing metaplasia (SPEM) cells.[34] SPEM cells replace the normal digestive enzyme-secreting chief cells and are accompanied by the expression of several genes and biomarkers that indicate transformation of chief cells to SPEM cells via paligenosis.[35][36] Analogous structural changes accompanied by the presence of paligenosis biomarkers have similarly been identified and studied in other cell environments, including neurons,[27] the liver,[1] kidney,[1] esophagus,[37] and pancreas,[36][38] often in the context of chronic injury conditions such as acid reflux in the case of Barrett's esophagus.[36] Studies have also described these indicators of paligenosis not only in mice, but also humans,[1][39] and other organisms including yeast, fruit flies, and axolotls.[39]

Role in cancer

Metaplastic cells are prone to adopting an abnormal state of growth known as dysplasia, eventually giving rise to tumors.[40][41] Paligenosis provides an explanation for how this occurs through what has become known as the cyclical hit model of tumorigenesis.[42][43] In this model, adult differentiated cells that have acquired mutations can be recruited back into a proliferative state via paligenosis. After healing, these cells can redifferentiate. However, under recurrent injury conditions that promote continued cycles of paligenosis, mutations and other chromosomal abnormalities can accumulate leading to loss of capacity for redifferentiation and conversion to uncontrolled cell growth and tumorigenesis.[23][36] Because of this, the resistance of cancer cells to various modes of treatment can often be attributed to cellular plasticity.[44][45] Continued investigation into paligenosis and related processes is thus motivated by the possibility of identifying treatable targets that can be useful for new cancer therapies.[46]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Willet, Spencer G; Lewis, Mark A; Miao, Zhi-Feng; Liu, Dengqun; Radyk, Megan D; Cunningham, Rebecca L; Burclaff, Joseph; Sibbel, Greg et al. (2018). "Regenerative proliferation of differentiated cells by mTORC 1-dependent paligenosis" (in en). The EMBO Journal 37 (7). doi:10.15252/embj.201798311. ISSN 0261-4189. PMID 29467218. 
  2. ↑ Cepelewicz, Jordana (2018-08-29). "To Heal Some Wounds, Adult Cells Turn More Fetal". https://www.quantamagazine.org/in-paligenosis-adult-cells-turn-fetal-to-heal-wounds-20180829/. 
  3. ↑ Thevenot, Verney D.; Perrault (1733) (in fr). Diverses Observations Anatomiques. Histoire de Academie Royale des Sciences ii. p. 7. https://scholar.google.com/scholar_lookup?journal=Histoire%20de%20VAcademie%20Royale%20des%20Sciences&title=Diverses%20Observations%20Anatomiques&author=%20Thevenot&author=D.%20Verney&author=%20Perrault&volume=ii&publication_year=1733&pages=7&. 
  4. ↑ Spallanzani, L. (1768). Montanari, Giovanni. ed. Prodromo di un' Opera da Imprimersi sopra le Riproduzioni Animali; Atti dell'Accademia delle scienze di Parigi. Modena: Marco Pagliarini.. p. 33. https://scholar.google.com/scholar_lookup?journal=Atti%20dell%27Accademia%20delle%20scienze%20di%20Parigi&title=Prodromo%20di%20un%E2%80%99%20Opera%20da%20Imprimersi%20sopra%20le%20Riproduzioni%20Animali&author=L.%20Spallanzani&publication_year=1768&. 
  5. ↑ Virchow, R (1884) (in da). Congrès périodique international des sciences médicales. 8me session, Copenhague. Copenhagen: Librairie Gyldendal. 
  6. ↑ Wachs, H. (1920) (in German). Über augenoperationen an amphibienlarven. Sitzungsberichte der Gesellschaft Naturforschender Freunde. pp. 133–154. 
  7. ↑ Vallette, M. (1929). "Regeneration du museau et territoires de regeneration chez les urodeles". Bull. Biol. Fr. Belg. 63: 95–148. https://scholar.google.com/scholar_lookup?journal=Bull.%20Biol.%20Fr.%20Belg.&title=Regeneration%20du%20museau%20et%20territoires%20de%20regeneration%20chez%20les%20urodeles&author=M.%20Vallette&volume=63&publication_year=1929&pages=95-148&. 
  8. ↑ Stone, L. S.; Chace, R. R. (1941). "Experimental studies on the regenerating lens and the eye in adult Triturus viridescens" (in en). The Anatomical Record 79 (3): 333–348. doi:10.1002/ar.1090790306. ISSN 0003-276X. https://onlinelibrary.wiley.com/doi/10.1002/ar.1090790306. 
  9. ↑ Briggs, Robert; King, Thomas J. (1952). "Transplantation of living nuclei from blastula cells into enucleated frogs' eggs" (in en). Proceedings of the National Academy of Sciences 38 (5): 455–463. doi:10.1073/pnas.38.5.455. ISSN 0027-8424. PMID 16589125. Bibcode: 1952PNAS...38..455B. 
  10. ↑ Chalkley, Donald Thomas (1954). "A quantitative histological analysis of forelimb regeneration in triturus viridescens" (in en). Journal of Morphology 94 (1): 21–70. doi:10.1002/jmor.1050940103. ISSN 0362-2525. https://onlinelibrary.wiley.com/doi/10.1002/jmor.1050940103. 
  11. ↑ Gurdon, J.B. (1960). "The developmental capacity of nuclei taken from differentiating endoderm cells of Xenopus laevis.". Journal of Embryology and Experimental Morphology 8: 505–526. PMID 13709842. 
  12. ↑ Gurdon, J.B. (1962). "The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles". Journal of Embryology and Experimental Morphology 10: 622–640. PMID 13951335. 
  13. ↑ Poss, Kenneth D.; Wilson, Lindsay G.; Keating, Mark T. (2002). "Heart Regeneration in Zebrafish" (in en). Science 298 (5601): 2188–2190. doi:10.1126/science.1077857. ISSN 0036-8075. PMID 12481136. Bibcode: 2002Sci...298.2188P. https://www.science.org/doi/10.1126/science.1077857. 
  14. ↑ Cai, Sa; Fu, Xiaobing; Sheng, Zhiyong (2007). "Dedifferentiation: A New Approach in Stem Cell Research" (in en). BioScience 57 (8): 655–662. doi:10.1641/B570805. ISSN 1525-3244. http://academic.oup.com/bioscience/article/57/8/655/284571/Dedifferentiation-A-New-Approach-in-Stem-Cell. 
  15. ↑ Adami, John George (1900). Huber, F. ed. On growth and overgrowth In "Festschrift" in honor of Abraham Jacobi, MD, LLD: to commemorate the seventieth anniversary of his birth, May sixth, 1900. New Rochelle, NY: Knickerbocker Press. pp. 422–432. https://scholar.google.com/scholar_lookup?title=%E2%80%9CFestschrift%E2%80%9D%20in%20honor%20of%20Abraham%20Jacobi,%20MD,%20LLD:%20to%20commemorate%20the%20seventieth%20anniversary%20of%20his%20birth,%20May%20sixth,%201900&author=JG%20Adami&publication_year=1900&. 
  16. ↑ Takahashi, Kazutoshi; Yamanaka, Shinya (2006). "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors" (in en). Cell 126 (4): 663–676. doi:10.1016/j.cell.2006.07.024. PMID 16904174. https://linkinghub.elsevier.com/retrieve/pii/S0092867406009767. 
  17. ↑ Vallone, Valeria Fernandez; Leprovots, Morgane; Strollo, Sandra; Vasile, Gabriela; Lefort, Anne; Libert, Frederick; Vassart, Gilbert; Garcia, Marie-Isabelle (2016). "Trop2 marks transient gastric fetal epithelium and adult regenerating cells after epithelial damage" (in en). Development 143 (9): 1452–1463. doi:10.1242/dev.131490. ISSN 1477-9129. PMID 26989172. 
  18. ↑ Nusse, Ysbrand M.; Savage, Adam K.; Marangoni, Pauline; Rosendahl-Huber, Axel K. M.; Landman, Tyler A.; de Sauvage, Frederic J.; Locksley, Richard M.; Klein, Ophir D. (2018). "Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche" (in en). Nature 559 (7712): 109–113. doi:10.1038/s41586-018-0257-1. ISSN 0028-0836. PMID 29950724. Bibcode: 2018Natur.559..109N. 
  19. ↑ Yui, Shiro; Azzolin, Luca; Maimets, Martti; Pedersen, Marianne Terndrup; Fordham, Robert P.; Hansen, Stine L.; Larsen, Hjalte L.; Guiu, Jordi et al. (2018). "YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration" (in en). Cell Stem Cell 22 (1): 35–49.e7. doi:10.1016/j.stem.2017.11.001. PMID 29249464. 
  20. ↑ Messal, Hendrik A; Cremona, Catherine A; Lan, Linxiang; Behrens, Axel (2018-04-03). "Paligenosis: prepare to regenerate!" (in en). The EMBO Journal 37 (7). doi:10.15252/embj.201899206. ISSN 0261-4189. PMID 29567644. 
  21. ↑ Mills, Jason C; Stanger, Ben Z; Sander, Maike (2019). "Nomenclature for cellular plasticity: are the terms as plastic as the cells themselves?" (in en). The EMBO Journal 38 (19). doi:10.15252/embj.2019103148. ISSN 0261-4189. PMID 31475380. 
  22. ↑ Johnson, Nicolette M.; Lengner, Christopher J. (2020). "MTORC1 and the Rebirth of Stemness" (in en). Developmental Cell 55 (2): 113–115. doi:10.1016/j.devcel.2020.10.001. PMID 33108751. https://linkinghub.elsevier.com/retrieve/pii/S1534580720307632. 
  23. ↑ 23.0 23.1 23.2 Miao, Zhi-Feng; Sun, Jing-Xu; Adkins-Threats, Mahliyah; Pang, Min-Jiao; Zhao, Jun-Hua; Wang, Xin; Tang, Kai-Wen; Wang, Zhen-Ning et al. (2021). "DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia" (in en). Gastroenterology 160 (1): 260–271.e10. doi:10.1053/j.gastro.2020.09.016. PMID 32956680. 
  24. ↑ 24.0 24.1 Miao, Zhi-Feng; Cho, Charles J.; Wang, Zhen-Ning; Mills, Jason C. (2021). "Autophagy repurposes cells during paligenosis" (in en). Autophagy 17 (2): 588–589. doi:10.1080/15548627.2020.1857080. ISSN 1554-8627. PMID 33280496. 
  25. ↑ Radyk, Megan D; Spatz, Lillian B; Peña, Bianca L; Brown, Jeffrey W; Burclaff, Joseph; Cho, Charles J; Kefalov, Yan; Shih, Chien-Cheng et al. (2021). "ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program" (in en). EMBO Reports 22 (9). doi:10.15252/embr.202051806. ISSN 1469-221X. PMID 34309175. 
  26. ↑ Willet, Spencer G.; Thanintorn, Nattapon; McNeill, Helen; Huh, Sung-Ho; Ornitz, David M.; Huh, Won Jae; Hoft, Stella G.; DiPaolo, Richard J. et al. (2023). "SOX9 Governs Gastric Mucous Neck Cell Identity and Is Required for Injury-Induced Metaplasia" (in en). Cellular and Molecular Gastroenterology and Hepatology 16 (3): 325–339. doi:10.1016/j.jcmgh.2023.05.009. PMID 37270061. 
  27. ↑ 27.0 27.1 Brown, Jeffrey W.; Cho, Charles J.; Mills, Jason C. (2022). "Paligenosis: Cellular Remodeling During Tissue Repair" (in en). Annual Review of Physiology 84 (1): 461–483. doi:10.1146/annurev-physiol-061121-035954. ISSN 0066-4278. PMID 34705482. 
  28. ↑ Cho, Charles J.; Nguyen, Thanh; Rougeau, Amala K.; Huang, Yang-Zhe; To, Sarah; Lin, Xiaobo; Thalalla Gamage, Supuni; Meier, Jordan L. et al. (2025). "Inhibition of Ribosome Biogenesis In Vivo Causes p53-Dependent Death and p53-Independent Dysfunction" (in en). Cellular and Molecular Gastroenterology and Hepatology 19 (7). doi:10.1016/j.jcmgh.2025.101496. PMID 40081569. 
  29. ↑ Viragova, Sara; Li, Dong; Klein, Ophir D. (2024). "Activation of fetal-like molecular programs during regeneration in the intestine and beyond". Cell Stem Cell 31 (7): 949–960. doi:10.1016/j.stem.2024.05.009. ISSN 1875-9777. PMID 38971147. 
  30. ↑ Miao, Zhi-Feng; Sun, Jing-Xu; Huang, Xuan-Zhang; Bai, Shi; Pang, Min-Jiao; Li, Jia-Yi; Chen, Han-Yu; Tong, Qi-Yue et al. (2024). "Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway" (in en). Developmental Cell 59 (9): 1175–1191.e7. doi:10.1016/j.devcel.2024.03.002. PMID 38521055. 
  31. ↑ Adkins-Threats, Mahliyah; Mills, Jason C (2022). "Cell plasticity in regeneration in the stomach and beyond" (in en). Current Opinion in Genetics & Development 75. doi:10.1016/j.gde.2022.101948. PMID 35809361. 
  32. ↑ Sáenz, José B.; Vargas, Nancy; Mills, Jason C. (2019). "Tropism for Spasmolytic Polypeptide-Expressing Metaplasia Allows Helicobacter pylori to Expand Its Intragastric Niche". Gastroenterology 156 (1): 160–174.e7. doi:10.1053/j.gastro.2018.09.050. ISSN 1528-0012. PMID 30287170. 
  33. ↑ Adkins-Threats, Mahliyah; Mills, Jason C (2022). "Cell plasticity in regeneration in the stomach and beyond" (in en). Current Opinion in Genetics & Development 75. doi:10.1016/j.gde.2022.101948. PMID 35809361. 
  34. ↑ Schmidt, P. H.; Lee, J. R.; Joshi, V.; Playford, R. J.; Poulsom, R.; Wright, N. A.; Goldenring, J. R. (1999). "Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma". Laboratory Investigation; A Journal of Technical Methods and Pathology 79 (6): 639–646. ISSN 0023-6837. PMID 10378506. 
  35. ↑ Weis, Victoria G.; Goldenring, James R. (2009). "Current understanding of SPEM and its standing in the preneoplastic process" (in en). Gastric Cancer 12 (4): 189–197. doi:10.1007/s10120-009-0527-6. ISSN 1436-3291. PMID 20047123. 
  36. ↑ 36.0 36.1 36.2 36.3 Jin, Ramon U.; Mills, Jason C. (2019). "The cyclical hit model: how paligenosis might establish the mutational landscape in Barrett's esophagus and esophageal adenocarcinoma" (in en). Current Opinion in Gastroenterology 35 (4): 363–370. doi:10.1097/MOG.0000000000000540. ISSN 0267-1379. PMID 31021922. 
  37. ↑ Busslinger, Georg A.; de Barbanson, Buys; Oka, Rurika; Weusten, Bas L. A.; de Maat, Michiel; van Hillegersberg, Richard; Brosens, Lodewijk A. A.; van Boxtel, Ruben et al. (2021). "Molecular characterization of Barrett's esophagus at single-cell resolution" (in en). Proceedings of the National Academy of Sciences 118 (47). doi:10.1073/pnas.2113061118. ISSN 0027-8424. PMID 34795059. Bibcode: 2021PNAS..11813061B. 
  38. ↑ Ma, Zhibo; Lytle, Nikki K.; Chen, Bob; Jyotsana, Nidhi; Novak, Sammy Weiser; Cho, Charles J.; Caplan, Leah; Ben-Levy, Olivia et al. (2022). "Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury" (in en). Gastroenterology 162 (2): 604–620.e20. doi:10.1053/j.gastro.2021.10.027. PMID 34695382. 
  39. ↑ 39.0 39.1 Miao, Zhi-Feng; Lewis, Mark A.; Cho, Charles J.; Adkins-Threats, Mahliyah; Park, Dongkook; Brown, Jeffrey W.; Sun, Jing-Xu; Burclaff, Joseph R. et al. (2020). "A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle" (in en). Developmental Cell 55 (2): 178–194.e7. doi:10.1016/j.devcel.2020.07.005. PMID 32768422. 
  40. ↑ Lim, Na Rae; Chung, Woo Chul (2023). "Helicobacter pylori -associated Chronic Atrophic Gastritis and Progression of Gastric Carcinogenesis" (in en). The Korean Journal of Gastroenterology 82 (4): 171–179. doi:10.4166/kjg.2023.097. ISSN 1598-9992. PMID 37876256. 
  41. ↑ Tong, Qi-Yue; Pang, Min-Jiao; Hu, Xiao-Hai; Huang, Xuan-Zhang; Sun, Jing-Xu; Wang, Xin-Yu; Burclaff, Joseph; Mills, Jason C. et al. (2024). "Gastric intestinal metaplasia: progress and remaining challenges" (in en). Journal of Gastroenterology 59 (4): 285–301. doi:10.1007/s00535-023-02073-9. ISSN 0944-1174. PMID 38242996. https://link.springer.com/10.1007/s00535-023-02073-9. 
  42. ↑ Jin, Ramon U.; Mills, Jason C. (2019). "The cyclical hit model: how paligenosis might establish the mutational landscape in Barrett's esophagus and esophageal adenocarcinoma" (in en). Current Opinion in Gastroenterology 35 (4): 363–370. doi:10.1097/MOG.0000000000000540. ISSN 0267-1379. PMID 31021922. 
  43. ↑ Zeng, Yongji; Jin, Ramon U. (2022). "Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer" (in en). Seminars in Cancer Biology 86 (Pt 3): 566–582. doi:10.1016/j.semcancer.2021.12.004. PMID 34933124. 
  44. ↑ Warrier, Neerada Meenakshi; Kelkar, Nachiket; Johnson, Carol Tresa; Govindarajan, Thirupugal; Prabhu, Vijendra; Kumar, Praveen (2023). "Understanding cancer stem cells and plasticity: Towards better therapeutics". European Journal of Cell Biology 102 (2). doi:10.1016/j.ejcb.2023.151321. ISSN 1618-1298. PMID 37137199. 
  45. ↑ Goldenring, James R.; Mills, Jason C. (2022). "Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond" (in en). Gastroenterology 162 (2): 415–430. doi:10.1053/j.gastro.2021.10.036. PMID 34728185. 
  46. ↑ Cho, Charles J.; Brown, Jeffrey W.; Mills, Jason C. (2024). "Origins of cancer: ain't it just mature cells misbehaving?". The EMBO Journal 43 (13): 2530–2551. doi:10.1038/s44318-024-00099-0. ISSN 1460-2075. PMID 38773319. 



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