1932

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 redif-ferentiation, 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.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-061121-035954
2022-02-10
2024-06-23
Loading full text...

Full text loading...

/deliver/fulltext/physiol/84/1/annurev-physiol-061121-035954.html?itemId=/content/journals/10.1146/annurev-physiol-061121-035954&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Waddington CH. 1940. Organisers and Genes Cambridge, UK: Cambridge Univ. Press
    [Google Scholar]
  2. 2. 
    Takahashi K, Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–76
    [Google Scholar]
  3. 3. 
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–72
    [Google Scholar]
  4. 4. 
    Spatz LB, Jin RU, Mills JC 2021. Cellular plasticity at the nexus of development and disease. Development 148:dev197392
    [Google Scholar]
  5. 5. 
    Shivdasani RA, Clevers H, de Sauvage FJ. 2021. Tissue regeneration: Reserve or reverse?. Science 371:784–86
    [Google Scholar]
  6. 6. 
    Rajagopal J, Stanger BZ. 2016. Plasticity in the adult: How should the Waddington diagram be applied to regenerating tissues?. Dev. Cell 36:133–37
    [Google Scholar]
  7. 7. 
    Chen T, Oh S, Gregory S, Shen X, Diehl AM 2020. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration. JCI Insight 5:e141024
    [Google Scholar]
  8. 8. 
    Luyten A, Zang C, Liu XS, Shivdasani RA. 2014. Active enhancers are delineated de novo during hematopoiesis, with limited lineage fidelity among specified primary blood cells. Genes Dev. 28:1827–39
    [Google Scholar]
  9. 9. 
    Fukushima T, Tanaka Y, Hamey FK, Chang CH, Oki T et al. 2019. Discrimination of dormant and active hematopoietic stem cells by G0 marker reveals dormancy regulation by cytoplasmic calcium. Cell Rep. 29:4144–58.e7
    [Google Scholar]
  10. 10. 
    Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. 2010. Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465:793–97
    [Google Scholar]
  11. 11. 
    Haas S, Hansson J, Klimmeck D, Loeffler D, Velten L et al. 2015. Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell 17:422–34
    [Google Scholar]
  12. 12. 
    Hume WJ, Potten CS. 1982. A long-lived thymidine pool in epithelial stem cells. Cell Tissue Kinet. 15:49–58
    [Google Scholar]
  13. 13. 
    Fujita R, Jamet S, Lean G, Cheng HCM, Hebert S et al. 2021. Satellite cell expansion is mediated by P-eIF2α-dependent Tacc3 translation. Development 148:dev194480
    [Google Scholar]
  14. 14. 
    Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M et al. 2010. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143:134–44
    [Google Scholar]
  15. 15. 
    Waddington CH. 1957. The Strategy of the Genes: A Discussion of Some Aspects of Theoretical Biology London: Allen & Unwin
    [Google Scholar]
  16. 16. 
    Bankaitis ED, Ha A, Kuo CJ, Magness ST. 2018. Reserve stem cells in intestinal homeostasis and injury. Gastroenterology 155:1348–61
    [Google Scholar]
  17. 17. 
    Barker N, van Es JH, Kuipers J, Kujala P, van den Born M et al. 2007. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–7
    [Google Scholar]
  18. 18. 
    Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N et al. 2009. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–65
    [Google Scholar]
  19. 19. 
    de Lau W, Barker N, Low TY, Koo BK, Li VS et al. 2011. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476:293–97
    [Google Scholar]
  20. 20. 
    Burclaff J, Mills JC. 2018. Plasticity of differentiated cells in wound repair and tumorigenesis, part II: skin and intestine. Dis. Model Mech. 11:dmm035071
    [Google Scholar]
  21. 21. 
    Li L, Clevers H 2010. Coexistence of quiescent and active adult stem cells in mammals. Science 327:542–45
    [Google Scholar]
  22. 22. 
    Willet SG, Mills JC. 2016. Stomach organ and cell lineage differentiation: from embryogenesis to adult homeostasis. Cell. Mol. Gastroenterol. Hepatol. 2:546–59
    [Google Scholar]
  23. 23. 
    Han S, Fink J, Jorg DJ, Lee E, Yum MK et al. 2019. Defining the identity and dynamics of adult gastric isthmus stem cells. Cell Stem Cell 25:342–56.e7
    [Google Scholar]
  24. 24. 
    Burclaff J, Willet SG, Saenz JB, Mills JC. 2020. Proliferation and differentiation of gastric mucous neck and chief cells during homeostasis and injury-induced metaplasia. Gastroenterology 158:598–609.e5
    [Google Scholar]
  25. 25. 
    Yan KS, Chia LA, Li X, Ootani A, Su J et al. 2012. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. PNAS 109:466–71
    [Google Scholar]
  26. 26. 
    Sangiorgi E, Capecchi MR. 2008. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40:915–20
    [Google Scholar]
  27. 27. 
    Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA 2011. Interconversion between intestinal stem cell populations in distinct niches. Science 334:1420–24
    [Google Scholar]
  28. 28. 
    Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME et al. 2011. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. PNAS 108:179–84
    [Google Scholar]
  29. 29. 
    Powell AE, Wang Y, Li Y, Poulin EJ, Means AL et al. 2012. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149:146–58
    [Google Scholar]
  30. 30. 
    Wong VWY, Stange DE, Page ME, Buczacki S, Wabik A et al. 2012. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 14:401–8
    [Google Scholar]
  31. 31. 
    Mills JC, Sansom OJ. 2015. Reserve stem cells: differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract. Sci. Signal 8:re8
    [Google Scholar]
  32. 32. 
    Jones JC, Brindley CD, Elder NH, Myers MG Jr., Rajala MW et al. 2019. Cellular plasticity of Defa4Cre-expressing paneth cells in response to notch activation and intestinal injury. Cell. Mol. Gastroenterol. Hepatol. 7:533–54
    [Google Scholar]
  33. 33. 
    Schmitt M, Schewe M, Sacchetti A, Feijtel D, van de Geer WS et al. 2018. Paneth cells respond to inflammation and contribute to tissue regeneration by acquiring stem-like features through SCF/c-Kit signaling. Cell Rep. 24:2312–28.e7
    [Google Scholar]
  34. 34. 
    Asfaha S, Hayakawa Y, Muley A, Stokes S, Graham TA et al. 2015. Krt19+/Lgr5 cells are radioresistant cancer-initiating stem cells in the colon and intestine. Cell Stem Cell 16:627–38
    [Google Scholar]
  35. 35. 
    Buczacki SJ, Zecchini HI, Nicholson AM, Russell R, Vermeulen L et al. 2013. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495:65–69
    [Google Scholar]
  36. 36. 
    Ishibashi F, Shimizu H, Nakata T, Fujii S, Suzuki K et al. 2018. Contribution of ATOH1+ cells to the homeostasis, repair, and tumorigenesis of the colonic epithelium. Stem Cell Rep. 10:27–42
    [Google Scholar]
  37. 37. 
    Tetteh PW, Basak O, Farin HF, Wiebrands K, Kretzschmar K et al. 2016. Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell 18:203–13
    [Google Scholar]
  38. 38. 
    Tian H, Biehs B, Warming S, Leong KG, Rangell L et al. 2011. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478:255–59
    [Google Scholar]
  39. 39. 
    Yan KS, Gevaert O, Zheng GXY, Anchang B, Probert CS et al. 2017. Intestinal enteroendocrine lineage cells possess homeostatic and injury-inducible stem cell activity. Cell Stem Cell 21:78–90.e6
    [Google Scholar]
  40. 40. 
    van Es JH, Wiebrands K, Lopez-Iglesias C, van de Wetering M, Zeinstra L et al. 2019. Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion. PNAS 116:26599–605
    [Google Scholar]
  41. 41. 
    Chandrakesan P, May R, Qu D, Weygant N, Taylor VE et al. 2015. Dclk1+ small intestinal epithelial tuft cells display the hallmarks of quiescence and self-renewal. Oncotarget 6:30876–86
    [Google Scholar]
  42. 42. 
    Weng PL, Aure MH, Maruyama T, Ovitt CE 2018. Limited regeneration of adult salivary glands after severe injury involves cellular plasticity. Cell Rep. 24:1464–70.e3
    [Google Scholar]
  43. 43. 
    Sangiorgi E, Capecchi MR. 2009. Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis. PNAS 106:7101–6
    [Google Scholar]
  44. 44. 
    Yanger K, Knigin D, Zong Y, Maggs L, Gu G et al. 2014. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15:340–49
    [Google Scholar]
  45. 45. 
    Wollny D, Zhao S, Everlien I, Lun X, Brunken J et al. 2016. Single-cell analysis uncovers clonal acinar cell heterogeneity in the adult pancreas. Dev. Cell 39:289–301
    [Google Scholar]
  46. 46. 
    Marescal O, Cheeseman IM. 2020. Cellular mechanisms and regulation of quiescence. Dev. Cell 55:259–71
    [Google Scholar]
  47. 47. 
    Grimont A, Leach SD, Chandwani R. 2021. Uncertain beginnings: acinar and ductal cell plasticity in the development of pancreatic cancer. Cell. Mol. Gastroenterol. Hepatol In press. https://doi.org/10.1016/j.jcmgh.2021.07.014
    [Crossref] [Google Scholar]
  48. 48. 
    Habbe N, Shi G, Meguid RA, Fendrich V, Esni F et al. 2008. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. PNAS 105:18913–18
    [Google Scholar]
  49. 49. 
    Shi G, Zhu L, Sun Y, Bettencourt R, Damsz B et al. 2009. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136:1368–78
    [Google Scholar]
  50. 50. 
    Baumgart M, Werther M, Bockholt A, Scheurer M, Ruschoff J et al. 2010. Genomic instability at both the base pair level and the chromosomal level is detectable in earliest PanIN lesions in tissues of chronic pancreatitis. Pancreas 39:1093–103
    [Google Scholar]
  51. 51. 
    Hill R, Calvopina JH, Kim C, Wang Y, Dawson DW et al. 2010. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 70:7114–24
    [Google Scholar]
  52. 52. 
    Bailey JM, Alsina J, Rasheed ZA, McAllister FM, Fu YY et al. 2014. DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 146:245–56
    [Google Scholar]
  53. 53. 
    Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L et al. 2007. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11:291–302
    [Google Scholar]
  54. 54. 
    Hruban RH, Adsay NV, Albores-Saavedra J, Anver MR, Biankin AV et al. 2006. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 66:95–106
    [Google Scholar]
  55. 55. 
    Tuveson DA, Hingorani SR. 2005. Ductal pancreatic cancer in humans and mice. Cold Spring Harb. Symp. Quant. Biol. 70:65–72
    [Google Scholar]
  56. 56. 
    Chen F, Jimenez RJ, Sharma K, Luu HY, Hsu BY et al. 2020. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration. Cell Stem Cell 26:27–33.e4
    [Google Scholar]
  57. 57. 
    Goldenring JR. 2018. Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. J. Pathol. 245:132–37
    [Google Scholar]
  58. 58. 
    Bockerstett KA, Lewis SA, Wolf KJ, Noto CN, Jackson NM et al. 2020. Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach. Gut 69:1027–38
    [Google Scholar]
  59. 59. 
    Schmidt PH, Lee JR, Joshi V, Playford RJ, Poulsom R et al. 1999. Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma. Lab. Investig. 79:639–46
    [Google Scholar]
  60. 60. 
    Jin RU, Mills JC 2019. The cyclical hit model: how paligenosis might establish the mutational landscape in Barrett's esophagus and esophageal adenocarcinoma. Curr. Opin. Gastroenterol. 35:363–70
    [Google Scholar]
  61. 61. 
    Halldorsdottir AM, Sigurdardottrir M, Jonasson JG, Oddsdottir M, Magnusson J et al. 2003. Spasmolytic polypeptide-expressing metaplasia (SPEM) associated with gastric cancer in Iceland. Dig. Dis. Sci. 48:431–41
    [Google Scholar]
  62. 62. 
    Lennerz JK, Kim SH, Oates EL, Huh WJ, Doherty JM et al. 2010. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma. Am. J. Pathol. 177:1514–33
    [Google Scholar]
  63. 63. 
    Saenz JB, Mills JC. 2018. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat. Rev. Gastroenterol. Hepatol. 15:257–73
    [Google Scholar]
  64. 64. 
    Adami JG. 1900. On growth and overgrowth and on the relationship between cell differentiation and proliferative capacity; its bearing upon the regeneration of tissues and the development of tumors. Festschrift in Honor of Abraham Jacobi, M.D., L.L.D.: To Commemorate the Seventieth Anniversary of his Birth, May Sixth, 1900422–32 New Rochelle, NY: Knickerbocker Press
    [Google Scholar]
  65. 65. 
    Willet SG, Lewis MA, Miao ZF, Liu D, Radyk MD et al. 2018. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J. 37:e98311
    [Google Scholar]
  66. 66. 
    Radyk MD, Spatz LB, Pena BL, Brown JW, Burclaff J et al. 2021. ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program. EMBO Rep. 22:e51806
    [Google Scholar]
  67. 67. 
    Meyer AR, Engevik AC, Willet SG, Williams JA, Zou Y et al. 2019. Cystine/glutamate antiporter (xCT) is required for chief cell plasticity after gastric injury. Cell. Mol. Gastroenterol. Hepatol. 8:379–405
    [Google Scholar]
  68. 68. 
    Petersen CP, Weis VG, Nam KT, Sousa JF, Fingleton B, Goldenring JR 2014. Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells. Gastroenterology 146:1727–38.e8
    [Google Scholar]
  69. 69. 
    Meyer AR, Engevik AC, Madorsky T, Belmont E, Stier MT et al. 2020. Group 2 innate lymphoid cells coordinate damage response in the stomach. Gastroenterology 159:2077–91.e8
    [Google Scholar]
  70. 70. 
    De Salvo C, Pastorelli L, Petersen CP, Butto LF, Buela KA et al. 2021. Interleukin 33 triggers early eosinophil-dependent events leading to metaplasia in a chronic model of gastritis-prone mice. Gastroenterology 160:302–16.e7
    [Google Scholar]
  71. 71. 
    Bockerstett KA, Petersen CP, Noto CN, Kuehm LM, Wong CF et al. 2020. Interleukin 27 protects from gastric atrophy and metaplasia during chronic autoimmune gastritis. Cell. Mol. Gastroenterol. Hepatol. 10:561–79
    [Google Scholar]
  72. 72. 
    Bockerstett KA, Osaki LH, Petersen CP, Cai CW, Wong CF et al. 2018. Interleukin-17A promotes parietal cell atrophy by inducing apoptosis. Cell. Mol. Gastroenterol. Hepatol. 5:678–90.e1
    [Google Scholar]
  73. 73. 
    Miao ZF, Lewis MA, Cho CJ, Adkins-Threats M, Park D et al. 2020. A dedicated evolutionarily conserved molecular network licenses differentiated cells to return to the cell cycle. Dev. Cell 55:178–94.e7
    [Google Scholar]
  74. 74. 
    Saera-Vila A, Kish PE, Louie KW, Grzegorski SJ, Klionsky DJ, Kahana A. 2016. Autophagy regulates cytoplasmic remodeling during cell reprogramming in a zebrafish model of muscle regeneration. Autophagy 12:1864–75
    [Google Scholar]
  75. 75. 
    Sarraf SA, Youle RJ. 2018. Parkin mediates mitophagy during beige-to-white fat conversion. Sci. Signal 11:eaat1082
    [Google Scholar]
  76. 76. 
    Lu X, Altshuler-Keylin S, Wang Q, Chen Y, Henrique Sponton C et al. 2018. Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism. Sci. Signal 11:eaap8526
    [Google Scholar]
  77. 77. 
    Altshuler-Keylin S, Shinoda K, Hasegawa Y, Ikeda K, Hong H et al. 2016. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24:402–19
    [Google Scholar]
  78. 78. 
    Espeillac C, Mitchell C, Celton-Morizur S, Chauvin C, Koka V et al. 2011. S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. J. Clin. Investig. 121:2821–32
    [Google Scholar]
  79. 79. 
    Crane ED, Wong W, Zhang H, O'Neil G, Crane JD. 2021. AMPK inhibits mTOR-driven keratinocyte proliferation after skin damage and stress. J. Investig. Dermatol. 141:2170–77.e3
    [Google Scholar]
  80. 80. 
    Brunkard JO. 2020. Exaptive evolution of target of rapamycin signaling in multicellular eukaryotes. Dev. Cell 54:142–55
    [Google Scholar]
  81. 81. 
    Johnson NM, Lengner CJ. 2020. MTORC1 and the rebirth of stemness. Dev. Cell 55:113–15
    [Google Scholar]
  82. 82. 
    Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW et al. 2014. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert. Nature 510:393–96
    [Google Scholar]
  83. 83. 
    Bohin N, McGowan KP, Keeley TM, Carlson EA, Yan KS, Samuelson LC 2020. Insulin-like growth factor-1 and mTORC1 signaling promote the intestinal regenerative response after irradiation injury. Cell. Mol. Gastroenterol. Hepatol. 10:797–810
    [Google Scholar]
  84. 84. 
    Wang S, Xia P, Ye B, Huang G, Liu J, Fan Z. 2013. Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Cell Stem Cell 13:617–25
    [Google Scholar]
  85. 85. 
    Miao ZF, Lewis MA, Cho CJ, Adkins-Threats M, Park D et al. 2020. A dedicated evolutionarily conserved molecular network licenses differentiated cells to return to the cell cycle. Dev. Cell 55:178–94.e7
    [Google Scholar]
  86. 86. 
    Tirone F, Shooter EM. 1989. Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene. PNAS 86:2088–92
    [Google Scholar]
  87. 87. 
    Vietor I, Huber LA. 2007. Role of TIS7 family of transcriptional regulators in differentiation and regeneration. Differentiation 75:891–97
    [Google Scholar]
  88. 88. 
    Garcia AM, Wakeman D, Lu J, Rowley C, Geisman T et al. 2014. Tis7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 307:G642–54
    [Google Scholar]
  89. 89. 
    Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I et al. 2009. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 458:1039–42
    [Google Scholar]
  90. 90. 
    Tummers B, Goedemans R, Pelascini LP, Jordanova ES, van Esch EM et al. 2015. The interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation. Nat. Commun. 6:6537
    [Google Scholar]
  91. 91. 
    Park G, Horie T, Kanayama T, Fukasawa K, Iezaki T et al. 2017. The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes. FEBS J. 284:784–95
    [Google Scholar]
  92. 92. 
    Onishi Y, Park G, Iezaki T, Horie T, Kanayama T et al. 2017. The transcriptional modulator Ifrd1 is a negative regulator of BMP-2-dependent osteoblastogenesis. Biochem. Biophys. Res. Commun. 482:329–34
    [Google Scholar]
  93. 93. 
    Andreev DE, O'Connor PB, Fahey C, Kenny EM, Terenin IM et al. 2015. Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression. eLife 4:e03971
    [Google Scholar]
  94. 94. 
    Zhao C, Datta S, Mandal P, Xu S, Hamilton T. 2010. Stress-sensitive regulation of IFRD1 mRNA decay is mediated by an upstream open reading frame. J. Biol. Chem. 285:8552–62
    [Google Scholar]
  95. 95. 
    Reiling JH, Hafen E. 2004. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18:2879–92
    [Google Scholar]
  96. 96. 
    Corradetti MN, Inoki K, Guan KL. 2005. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J. Biol. Chem. 280:9769–72
    [Google Scholar]
  97. 97. 
    DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. 2008. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14–3–3 shuttling. Genes Dev. 22:239–51
    [Google Scholar]
  98. 98. 
    Hernandez G, Lal H, Fidalgo M, Guerrero A, Zalvide J et al. 2011. A novel cardioprotective p38-MAPK/mTOR pathway. Exp. Cell Res. 317:2938–49
    [Google Scholar]
  99. 99. 
    Pieri BL, Souza DR, Luciano TF, Marques SO, Pauli JR et al. 2014. Effects of physical exercise on the P38MAPK/REDD1/14-3-3 pathways in the myocardium of diet-induced obesity rats. Horm. Metab. Res. 46:621–27
    [Google Scholar]
  100. 100. 
    Favier FB, Costes F, Defour A, Bonnefoy R, Lefai E et al. 2010. Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298:R1659–66
    [Google Scholar]
  101. 101. 
    Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X. 2010. Structural analysis and functional implications of the negative mTORC1 regulator REDD1. Biochemistry 49:2491–501
    [Google Scholar]
  102. 102. 
    Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D 2003. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5:578–81
    [Google Scholar]
  103. 103. 
    Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P et al. 2003. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5:559–65
    [Google Scholar]
  104. 104. 
    Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M et al. 2003. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11:1457–66
    [Google Scholar]
  105. 105. 
    Castro AF, Rebhun JF, Clark GJ, Quilliam LA 2003. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem. 278:32493–96
    [Google Scholar]
  106. 106. 
    Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13:1259–68
    [Google Scholar]
  107. 107. 
    Inoki K, Li Y, Xu T, Guan KL. 2003. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17:1829–34
    [Google Scholar]
  108. 108. 
    Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J 2005. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15:702–13
    [Google Scholar]
  109. 109. 
    Radyk MD, Burclaff J, Willet SG, Mills JC. 2018. Metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells. Gastroenterology 154:839–43.e2
    [Google Scholar]
  110. 110. 
    Jeong S, Choi E, Petersen CP, Roland JT, Federico A et al. 2017. Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis. United Eur. Gastroenterol. J. 5:37–44
    [Google Scholar]
  111. 111. 
    Riera KM, Jang B, Min J, Roland JT, Yang Q et al. 2020. Trop2 is upregulated in the transition to dysplasia in the metaplastic gastric mucosa. J. Pathol. 251:336–47
    [Google Scholar]
  112. 112. 
    He M, Ding Y, Chu C, Tang J, Xiao Q, Luo ZG 2016. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury. PNAS 113:11324–29
    [Google Scholar]
  113. 113. 
    Abe N, Borson SH, Gambello MJ, Wang F, Cavalli V 2010. Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J. Biol. Chem. 285:28034–43
    [Google Scholar]
  114. 114. 
    Carlin D, Halevi AE, Ewan EE, Moore AM, Cavalli V 2019. Nociceptor deletion of Tsc2 enhances axon regeneration by inducing a conditioning injury response in dorsal root ganglia. eNeuro 6:ENEURO.0168-19.2019
    [Google Scholar]
  115. 115. 
    Gey M, Wanner R, Schilling C, Pedro MT, Sinske D, Knoll B 2016. Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury. Open Biol. 6:160091
    [Google Scholar]
  116. 116. 
    Otsubo Y, Yamashita A, Ohno H, Yamamoto M. 2014. S. pombe TORC1 activates the ubiquitin-proteasomal degradation of the meiotic regulator Mei2 in cooperation with Pat1 kinase. J. Cell Sci. 127:2639–46
    [Google Scholar]
  117. 117. 
    Nakase Y, Fukuda K, Chikashige Y, Tsutsumi C, Morita D et al. 2006. A defect in protein farnesylation suppresses a loss of Schizosaccharomyces pombetsc2+, a homolog of the human gene predisposing to tuberous sclerosis complex. Genetics 173:569–78
    [Google Scholar]
  118. 118. 
    Matsumoto S, Bandyopadhyay A, Kwiatkowski DJ, Maitra U, Matsumoto T 2002. Role of the Tsc1-Tsc2 complex in signaling and transport across the cell membrane in the fission yeast Schizosaccharomyces pombe. Genetics 161:1053–63
    [Google Scholar]
  119. 119. 
    Valbuena N, Moreno S. 2010. TOR and PKA pathways synergize at the level of the Ste11 transcription factor to prevent mating and meiosis in fission yeast. PLOS ONE 5:e11514
    [Google Scholar]
  120. 120. 
    Alvarez B, Moreno S. 2006. Fission yeast Tor2 promotes cell growth and represses cell differentiation. J. Cell Sci. 119:4475–85
    [Google Scholar]
  121. 121. 
    Matsuhara H, Yamamoto A. 2016. Autophagy is required for efficient meiosis progression and proper meiotic chromosome segregation in fission yeast. Genes Cells 21:65–87
    [Google Scholar]
  122. 122. 
    Nakashima A, Hasegawa T, Mori S, Ueno M, Tanaka S et al. 2006. A starvation-specific serine protease gene, isp6+, is involved in both autophagy and sexual development in Schizosaccharomyces pombe. Curr. Genet. 49:403–13
    [Google Scholar]
  123. 123. 
    Carr M, Leadbeater BS, Hassan R, Nelson M, Baldauf SL 2008. Molecular phylogeny of choanoflagellates, the sister group to Metazoa. PNAS 105:16641–46
    [Google Scholar]
  124. 124. 
    Ruiz-Trillo I, Roger AJ, Burger G, Gray MW, Lang BF 2008. A phylogenomic investigation into the origin of metazoa. Mol. Biol. Evol. 25:664–72
    [Google Scholar]
  125. 125. 
    Brunet T, King N. 2017. The origin of animal multicellularity and cell differentiation. Dev. Cell 43:124–40
    [Google Scholar]
  126. 126. 
    Levin TC, Greaney AJ, Wetzel L, King N. 2014. The rosetteless gene controls development in the choanoflagellate S. rosetta. eLife 3:e04070
    [Google Scholar]
  127. 127. 
    Leadbeater BSC. 2015. The Choanoflagellates: Evolution, Biology, and Ecology Cambridge, UK: Cambridge Univ. Press
    [Google Scholar]
  128. 128. 
    Laundon D, Larson BT, McDonald K, King N, Burkhardt P 2019. The architecture of cell differentiation in choanoflagellates and sponge choanocytes. PLOS Biol. 17:e3000226
    [Google Scholar]
  129. 129. 
    Arendt D, Denes AS, Jekely G, Tessmar-Raible K. 2008. The evolution of nervous system centralization. Philos. Trans. R. Soc. B 363:1523–28
    [Google Scholar]
  130. 130. 
    Strassmann JE, Zhu Y, Queller DC. 2000. Altruism and social cheating in the social amoeba Dictyostelium discoideum. Nature 408:965–67
    [Google Scholar]
  131. 131. 
    Nichols JM, Antolovic V, Reich JD, Brameyer S, Paschke P, Chubb JR 2020. Cell and molecular transitions during efficient dedifferentiation. eLife 9:e55435
    [Google Scholar]
  132. 132. 
    Mills JC, Taghert PH. 2012. Scaling factors: transcription factors regulating subcellular domains. Bioessays 34:10–16
    [Google Scholar]
  133. 133. 
    Michod RE. 2007. Evolution of individuality during the transition from unicellular to multicellular life. PNAS 104:Suppl. 18613–18
    [Google Scholar]
  134. 134. 
    Slack JM. 2017. Animal regeneration: ancestral character or evolutionary novelty?. EMBO Rep. 18:1497–508
    [Google Scholar]
  135. 135. 
    Ikeuchi M, Ogawa Y, Iwase A, Sugimoto K 2016. Plant regeneration: cellular origins and molecular mechanisms. Development 143:1442–51
    [Google Scholar]
  136. 136. 
    Trigos AS, Pearson RB, Papenfuss AT, Goode DL. 2017. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. PNAS 114:6406–11
    [Google Scholar]
  137. 137. 
    Bussey KJ, Cisneros LH, Lineweaver CH, Davies PCW. 2017. Ancestral gene regulatory networks drive cancer. PNAS 114:6160–62
    [Google Scholar]
  138. 138. 
    Bischoff JR, Casso D, Beach D 1992. Human p53 inhibits growth in Schizosaccharomyces pombe. Mol. Cell. Biol. 12:1405–11
    [Google Scholar]
  139. 139. 
    Miao ZF, Cho CJ, Wang ZN, Mills JC 2020. Autophagy repurposes cells during paligenosis. Autophagy 17:588–89
    [Google Scholar]
  140. 140. 
    Kon N, Ou Y, Wang SJ, Li H, Rustgi AK, Gu W. 2021. mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression. Genes Dev. 35:59–64
    [Google Scholar]
  141. 141. 
    Carriere C, Young AL, Gunn JR, Longnecker DS, Korc M. 2009. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382:561–65
    [Google Scholar]
  142. 142. 
    Huang H, Daniluk J, Liu Y, Chu J, Li Z et al. 2014. Oncogenic K-Ras requires activation for enhanced activity. Oncogene 33:532–35
    [Google Scholar]
  143. 143. 
    Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S et al. 2012. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Investig. 122:639–53
    [Google Scholar]
  144. 144. 
    Mills JC, Stanger BZ, Sander M. 2019. Nomenclature for cellular plasticity: Are the terms as plastic as the cells themselves?. EMBO J. 38:e103148
    [Google Scholar]
  145. 145. 
    Rehman SK, Haynes J, Collignon E, Brown KR, Wang Y et al. 2021. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184:226–42.e21
    [Google Scholar]
  146. 146. 
    Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H et al. 2009. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15:701–6
    [Google Scholar]
  147. 147. 
    Giandomenico SL, Mierau SB, Gibbons GM, Wenger LMD, Masullo L et al. 2019. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat. Neurosci. 22:669–79
    [Google Scholar]
  148. 148. 
    Gindele JA, Kiechle T, Benediktus K, Birk G, Brendel M et al. 2020. Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture. Sci. Rep. 10:6257
    [Google Scholar]
  149. 149. 
    VanDussen KL, Marinshaw JM, Shaikh N, Miyoshi H, Moon C et al. 2015. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64:911–20
    [Google Scholar]
  150. 150. 
    Alexander KL, Serrano CA, Chakraborty A, Nearing M, Council LN et al. 2020. Modulation of glycosyltransferase ST6Gal-I in gastric cancer-derived organoids disrupts homeostatic epithelial cell turnover. J. Biol. Chem. 295:14153–63
    [Google Scholar]
  151. 151. 
    Yin X, Mead BE, Safaee H, Langer R, Karp JM, Levy O. 2016. Engineering stem cell organoids. Cell Stem Cell 18:25–38
    [Google Scholar]
  152. 152. 
    Chen M-S, Lo Y-H, Butkus J, Zou W, Tseng Y-J et al. 2018. Gfi1-expressing Paneth cells revert to stem cells following intestinal injury. bioRxiv 364133. https://doi.org/10.1101/364133
    [Crossref] [Google Scholar]
  153. 153. 
    Ma Z, Lytle NK, Chen B, Jyotsana N, Novak SWet al 2021. Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury. Gastroenterology In press. https://www.doi.org/10.1053/j.gastro.2021.10.027
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-physiol-061121-035954
Loading
/content/journals/10.1146/annurev-physiol-061121-035954
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error