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Annual Review of Cell and Developmental Biology

Volume 40, 2024

Thymic Mimetic Cells: Ontogeny as Immunology

Abstract

Medullary thymic epithelial cells (mTECs) generate immunological self-tolerance by ectopically expressing peripheral-tissue antigens (PTAs) within the thymus to preview the peripheral self to maturing T cells. Recent work, drawing inspiration from old histological observations, has shown that subtypes of mTECs, collectively termed mimetic cells, co-opt developmental programs from throughout the organism to express biologically coherent groups of PTAs. Here, we review key aspects of mimetic cells, especially as they relate to the larger contexts of molecular, cellular, developmental, and evolutionary biology. We highlight lineage-defining transcription factors as key regulators of mimetic cells and speculate as to what other factors, including Aire and the chromatin potential of mTECs, permit mimetic cell differentiation and function. Last, we consider what mimetic cells can teach us about not only the thymus but also other tissues.

Keyword(s): autoimmunity, mimetic cell, mTEC, thymus, tolerance, T cell
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2024-10-02
2025-04-28
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Literature Cited

  1. Aaltonen J, Björses P, Perheentupa J, Horelli-Kuitunen N, Palotie A, et al. 1997.. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. . Nat. Genet. 17::399–403
     [Crossref] [Google Scholar]
  2. Abramson J, Dobes J, Lyu M, Sonnenberg GF. 2024.. The emerging family of RORγt+ antigen-presenting cells. . Nat. Rev. Immunol. 24::64–77
     [Crossref] [Google Scholar]
  3. Abramson J, Giraud M, Benoist C, Mathis D. 2010.. Aire's partners in the molecular control of immunological tolerance. . Cell 140::123–35
     [Crossref] [Google Scholar]
  4. Akagbosu B, Tayyebi Z, Shibu G, Paucar Iza YA, Deep D, et al. 2022.. Novel antigen presenting cell imparts Treg-dependent tolerance to gut microbiota. . Nature 610::752–60
     [Crossref] [Google Scholar]
  5. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, et al. 2002.. Projection of an immunological self shadow within the thymus by the aire protein. . Science 298::1395–401
     [Crossref] [Google Scholar]
  6. Antonia SJ, Geiger T, Miller J, Flavell RA. 1995.. Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein. . Int. Immunol. 7::715–25
     [Crossref] [Google Scholar]
  7. Ashby KM, Hogquist KA. 2024.. A guide to thymic selection of T cells. . Nat. Rev. Immunol. 24::103–17. Author correction . 2023.. Nat. Rev. Immunol. 23::697
     [Google Scholar]
  8. Bansal K, Michelson DA, Ramirez RN, Viny AD, Levine RL, et al. 2021.. Aire regulates chromatin looping by evicting CTCF from domain boundaries and favoring accumulation of cohesin on superenhancers. . PNAS 118::e2110991118
     [Crossref] [Google Scholar]
  9. Bansal K, Yoshida H, Benoist C, Mathis D. 2017.. The transcriptional regulator Aire binds to and activates super-enhancers. . Nat. Immunol. 18::263–73
     [Crossref] [Google Scholar]
  10. Baran-Gale J, Morgan MD, Maio S, Dhalla F, Calvo-Asensio I, et al. 2020.. Ageing compromises mouse thymus function and remodels epithelial cell differentiation. . eLife 9::e56221
     [Crossref] [Google Scholar]
  11. Bautista JL, Cramer NT, Miller CN, Chavez J, Berrios DI, et al. 2021.. Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla. . Nat. Commun. 12::1096
     [Crossref] [Google Scholar]
  12. Benitez AA, Khalil-Aguero S, Nandakumar A, Gupta NT, Zhang W, et al. 2020.. Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses. . Commun. Biol. 3::355
     [Crossref] [Google Scholar]
  13. Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, et al. 2006.. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. . Nature 441::992–96
     [Crossref] [Google Scholar]
  14. Bonfanti P, Claudinot S, Amici AW, Farley A, Blackburn CC, et al. 2010.. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. . Nature 466::978–82
     [Crossref] [Google Scholar]
  15. Bornstein C, Nevo S, Giladi A, Kadouri N, Pouzolles M, et al. 2018.. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. . Nature 559::622–26
     [Crossref] [Google Scholar]
  16. Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, et al. 2015.. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. . Nat. Immunol. 16::933–41
     [Crossref] [Google Scholar]
  17. Brown CC, Rudensky AY. 2023.. Spatiotemporal regulation of peripheral T cell tolerance. . Science 380::472–78
     [Crossref] [Google Scholar]
  18. Chen L, Toke NH, Luo S, Vasoya RP, Fullem RL, et al. 2019.. A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity. . Nat. Genet. 51::777–85
     [Crossref] [Google Scholar]
  19. Danso-Abeam D, Staats KA, Franckaert D, Van Den Bosch L, Liston A, et al. 2013.. Aire mediates thymic expression and tolerance of pancreatic antigens via an unconventional transcriptional mechanism. . Eur. J. Immunol. 43::75–84
     [Crossref] [Google Scholar]
  20. Derbinski J, Pinto S, Rosch S, Hexel K, Kyewski B. 2008.. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. . PNAS 105::657–62
     [Crossref] [Google Scholar]
  21. Devoss J, Hou Y, Johannes K, Lu W, Liou GI, et al. 2006.. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. . J. Exp. Med. 203::2727–35
     [Crossref] [Google Scholar]
  22. Dhalla F, Baran-Gale J, Maio S, Chappell L, Hollander GA, et al. 2020.. Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells. . EMBO J. 39::e101828
     [Crossref] [Google Scholar]
  23. Dobes J, Ben-Nun O, Binyamin A, Stoler-Barak L, Oftedal BE, et al. 2022.. Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans. . Nat. Immunol. 23::1098–108
     [Crossref] [Google Scholar]
  24. Farr AG, Dooley JL, Erickson M. 2002.. Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation. . Immunol. Rev. 189::20–27
     [Crossref] [Google Scholar]
  25. Farr AG, Rudensky A. 1998.. Medullary thymic epithelium: a mosaic of epithelial “self”?. J. Exp. Med. 188::1–4
     [Crossref] [Google Scholar]
  26. Ferre EM, Rose SR, Rosenzweig SD, Burbelo PD, Romito KR, et al. 2016.. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. . JCI Insight 1::e88782
     [Crossref] [Google Scholar]
  27. Gardner JM, DeVoss JJ, Friedman RS, Wong DJ, Tan YX, et al. 2008.. Deletional tolerance mediated by extrathymic Aire-expressing cells. . Science 321::843–47
     [Crossref] [Google Scholar]
  28. Gardner JM, Liston A. 2022.. RORγt-lineage APCs: the Aire apparent. . Sci. Immunol. 7::eade9240
     [Crossref] [Google Scholar]
  29. Gardner JM, Metzger TC, McMahon EJ, Au-Yeung BB, Krawisz AK, et al. 2013.. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4+ T cells. . Immunity 39::560–72
     [Crossref] [Google Scholar]
  30. Gavanescu I, Kessler B, Ploegh H, Benoist C, Mathis D. 2007.. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. . PNAS 104::4583–87
     [Crossref] [Google Scholar]
  31. Gebert A, Fassbender S, Werner K, Weissferdt A. 1999.. The development of M cells in Peyer's patches is restricted to specialized dome-associated crypts. . Am. J. Pathol. 154::1573–82
     [Crossref] [Google Scholar]
  32. Gillis-Buck E, Miller H, Sirota M, Sanders SJ, Ntranos V, et al. 2021.. Extrathymic Aire-expressing cells support maternal-fetal tolerance. . Sci. Immunol. 6::eabf1968
     [Crossref] [Google Scholar]
  33. Giraud M, Jmari N, Du L, Carallis F, Nieland TJ, et al. 2014.. An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. . PNAS 111::1491–96
     [Crossref] [Google Scholar]
  34. Giraud M, Yoshida H, Abramson J, Rahl PB, Young RA, et al. 2012.. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. . PNAS 109::535–40
     [Crossref] [Google Scholar]
  35. Givony T, Leshkowitz D, Del Castillo D, Nevo S, Kadouri N, et al. 2023.. Thymic mimetic cells function beyond self-tolerance. . Nature 622::164–72
     [Crossref] [Google Scholar]
  36. Gu B, Lambert JP, Cockburn K, Gingras AC, Rossant J. 2017.. AIRE is a critical spindle-associated protein in embryonic stem cells. . eLife 6::e28131
     [Crossref] [Google Scholar]
  37. Gu B, Zhang J, Chen Q, Tao B, Wang W, et al. 2010.. Aire regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells. . Biochem. Biophys. Res. Commun. 394::418–23
     [Crossref] [Google Scholar]
  38. Guha M, Saare M, Maslovskaja J, Kisand K, Liiv I, et al. 2017.. DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes. . J. Biol. Chem. 292::6542–54
     [Crossref] [Google Scholar]
  39. Gunther T, Chen ZF, Kim J, Priemel M, Rueger JM, et al. 2000.. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. . Nature 406::199–203
     [Crossref] [Google Scholar]
  40. Hassall AH. 1846.. The Microscopic Anatomy of the Human Body: In Health and Disease. London:: S. Highley
     [Google Scholar]
  41. Herzig Y, Nevo S, Bornstein C, Brezis MR, Ben-Hur S, et al. 2017.. Transcriptional programs that control expression of the autoimmune regulator gene Aire. . Nat. Immunol. 18::161–72
     [Crossref] [Google Scholar]
  42. Jolicoeur C, Hanahan D, Smith KM. 1994.. T-cell tolerance toward a transgenic β-cell antigen and transcription of endogenous pancreatic genes in thymus. . PNAS 91::6707–11
     [Crossref] [Google Scholar]
  43. Joung J, Ma S, Tay T, Geiger-Schuller KR, Kirchgatterer PC, et al. 2023.. A transcription factor atlas of directed differentiation. . Cell 186::209–29
     [Crossref] [Google Scholar]
  44. Kaiser C, Bradu A, Gamble N, Caldwell JA, Koh AS. 2022.. AIRE in context: leveraging chromatin plasticity to trigger ectopic gene expression. . Immunol. Rev. 305::59–76
     [Crossref] [Google Scholar]
  45. Kedmi R, Najar TA, Mesa KR, Grayson A, Kroehling L, et al. 2022.. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation. . Nature 610::737–43
     [Crossref] [Google Scholar]
  46. Khan IS, Mouchess ML, Zhu ML, Conley B, Fasano KJ, et al. 2014.. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. . J. Exp. Med. 211::761–68
     [Crossref] [Google Scholar]
  47. Kirchner T, Tzartos S, Hoppe F, Schalke B, Wekerle H, et al. 1988.. Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. . Am. J. Pathol. 130::268–80
     [Google Scholar]
  48. Klein L, Kyewski B, Allen PM, Hogquist KA. 2014.. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). . Nat. Rev. Immunol. 14::377–91
     [Crossref] [Google Scholar]
  49. Knoop KA, Kumar N, Butler BR, Sakthivel SK, Taylor RT, et al. 2009.. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. . J. Immunol. 183::5738–47
     [Crossref] [Google Scholar]
  50. Koh AS, Miller EL, Buenrostro JD, Moskowitz DM, Wang J, et al. 2018.. Rapid chromatin repression by Aire provides precise control of immune tolerance. . Nat. Immunol. 19::162–72
     [Crossref] [Google Scholar]
  51. Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, et al. 2005.. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. . J. Immunol. 174::1862–70
     [Crossref] [Google Scholar]
  52. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. 2003.. Aire regulates negative selection of organ-specific T cells. . Nat. Immunol. 4::350–54
     [Crossref] [Google Scholar]
  53. Liu Z, Farley A, Chen L, Kirby BJ, Kovacs CS, et al. 2010.. Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions. . PLOS Genet. 6::e1001251
     [Crossref] [Google Scholar]
  54. Lyu M, Suzuki H, Kang L, Gaspal F, Zhou W, et al. 2022.. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. . Nature 610::744–51
     [Crossref] [Google Scholar]
  55. Mayer CE, Zuklys S, Zhanybekova S, Ohigashi I, Teh HY, et al. 2016.. Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla. . Eur. J. Immunol. 46::846–56
     [Crossref] [Google Scholar]
  56. Mayer S. 1888.. Zur Lehre von der Schilddrüse und Thymus bei den Amphibien. . Anat. Anz. 3::97–103
     [Google Scholar]
  57. Medawar PB. 1963.. Discussion: Role of the thymus in the origin of immunological competence. . In The Immunologically Competent Cell: Its Nature and Origin, ed. GEW Wolstenholme, J Knight , p. 70. Boston:: Little Brown
     [Google Scholar]
  58. Meredith M, Zemmour D, Mathis D, Benoist C. 2015.. Aire controls gene expression in the thymic epithelium with ordered stochasticity. . Nat. Immunol. 16::942–49
     [Crossref] [Google Scholar]
  59. Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, et al. 2013.. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. . Cell Rep. 5::166–79
     [Crossref] [Google Scholar]
  60. Michelson DA, Benoist C, Mathis D. 2022a.. CTLA-4 on thymic epithelial cells complements Aire for T cell central tolerance. . PNAS 119::e2215474119
     [Crossref] [Google Scholar]
  61. Michelson DA, Hase K, Kaisho T, Benoist C, Mathis D. 2022b.. Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. . Cell 185::2542–58
     [Crossref] [Google Scholar]
  62. Michelson DA, Mathis D. 2022.. Thymic mimetic cells: tolerogenic masqueraders. . Trends Immunol. 43::782–91
     [Crossref] [Google Scholar]
  63. Michelson DA, Zuo C, Verzi M, Benoist C, Mathis D. 2023.. Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus. . J. Exp. Med. 220::e20230461
     [Crossref] [Google Scholar]
  64. Miller CN, Proekt I, von Moltke J, Wells KL, Rajpurkar AR, et al. 2018.. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. . Nature 559::627–31
     [Crossref] [Google Scholar]
  65. Morimoto J, Matsumoto M, Miyazawa R, Yoshida H, Tsuneyama K, et al. 2022.. Aire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity. . Cell Rep. 38::110384
     [Crossref] [Google Scholar]
  66. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, et al. 1997.. Positional cloning of the APECED gene. . Nat. Genet. 17::393–98
     [Crossref] [Google Scholar]
  67. Nishikawa Y, Hirota F, Yano M, Kitajima H, Miyazaki J, et al. 2010.. Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. . J. Exp. Med. 207::963–71
     [Crossref] [Google Scholar]
  68. Nishikawa Y, Nishijima H, Matsumoto M, Morimoto J, Hirota F, et al. 2014.. Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program. . J. Immunol. 192::2585–92
     [Crossref] [Google Scholar]
  69. Nusser A, Sagar, Swann JB, Krauth B, Diekhoff D, et al. 2022.. Developmental dynamics of two bipotent thymic epithelial progenitor types. . Nature 606::165–71
     [Crossref] [Google Scholar]
  70. Panneck AR, Rafiq A, Schutz B, Soultanova A, Deckmann K, et al. 2014.. Cholinergic epithelial cell with chemosensory traits in murine thymic medulla. . Cell Tissue Res. 358::737–48
     [Crossref] [Google Scholar]
  71. Park JE, Botting RA, Dominguez CC, Popescu DM, Lavaert M, et al. 2020.. A cell atlas of human thymic development defines T cell repertoire formation. . Science 367::eaay3224
     [Crossref] [Google Scholar]
  72. Policheni AN, Teh CE, Robbins A, Tuzlak S, Strasser A, et al. 2022.. PD-1 cooperates with AIRE-mediated tolerance to prevent lethal autoimmune disease. . PNAS 119::e2120149119
     [Crossref] [Google Scholar]
  73. Proekt I, Miller CN, Jeanne M, Fasano KJ, Moon JJ, et al. 2016.. LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity. . J. Clin. Investig. 126::3758–71
     [Crossref] [Google Scholar]
  74. Remak R. 1855.. Untersuchungen über die Entwickelung der Wirbelthiere. London:: G. Reimer
     [Google Scholar]
  75. Rodewald HR. 2008.. Thymus organogenesis. . Annu. Rev. Immunol. 26::355–88
     [Crossref] [Google Scholar]
  76. Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C. 2001.. Thymus medulla consisting of epithelial islets each derived from a single progenitor. . Nature 414::763–68
     [Crossref] [Google Scholar]
  77. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. 2006.. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. . Nature 441::988–91
     [Crossref] [Google Scholar]
  78. Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, et al. 2007.. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. . J. Exp. Med. 204::1267–72
     [Crossref] [Google Scholar]
  79. Rubin SA, Baron CS, Pessoa RC, Duran M, Corbin AF, et al. 2022.. Single-cell analyses reveal early thymic progenitors and pre-B cells in zebrafish. . J. Exp. Med. 219::e20220038
     [Crossref] [Google Scholar]
  80. Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, et al. 2014.. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. . Genome Res. 24::1918–31
     [Crossref] [Google Scholar]
  81. Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, et al. 2015.. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. . Cell 163::975–87
     [Crossref] [Google Scholar]
  82. Tao W, Ye Z, Wei Y, Wang J, Yang W, et al. 2023.. Insm1 regulates mTEC development and immune tolerance. . Cell. Mol. Immunol. 20::1472–86
     [Crossref] [Google Scholar]
  83. Tomofuji Y, Takaba H, Suzuki HI, Benlaribi R, Martinez CDP, et al. 2020.. Chd4 choreographs self-antigen expression for central immune tolerance. . Nat. Immunol. 21::892–901
     [Crossref] [Google Scholar]
  84. Villasenor J, Besse W, Benoist C, Mathis D. 2008.. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. . PNAS 105::15854–59
     [Crossref] [Google Scholar]
  85. Wang J, Lareau CA, Bautista JL, Gupta AR, Sandor K, et al. 2021.. Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium. . Sci. Immunol. 6::eabl5053
     [Crossref] [Google Scholar]
  86. Waterfield M, Khan IS, Cortez JT, Fan U, Metzger T, et al. 2014.. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. . Nat. Immunol. 15::258–65
     [Crossref] [Google Scholar]
  87. Watney H. 1882.. The minute anatomy of the thymus. . Philos. Trans. R. Soc. 173::1063–123
     [Crossref] [Google Scholar]
  88. Wells KL, Miller CN, Gschwind AR, Wei W, Phipps JD, et al. 2020.. Combined transient ablation and single-cell RNA-sequencing reveals the development of medullary thymic epithelial cells. . eLife 9::e60188
     [Crossref] [Google Scholar]
  89. Wu XS, He XY, Ipsaro JJ, Huang YH, Preall JB, et al. 2022.. OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage. . Nature 607::169–75
     [Crossref] [Google Scholar]
  90. Yamano T, Dobes J, Voboril M, Steinert M, Brabec T, et al. 2019.. Aire-expressing ILC3-like cells in the lymph node display potent APC features. . J. Exp. Med. 216::1027–37
     [Crossref] [Google Scholar]
  91. Yoshida H, Bansal K, Schaefer U, Chapman T, Rioja I, et al. 2015.. Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells. . PNAS 112::E4448–57
     [Google Scholar]
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Thymic Mimetic Cells: Ontogeny as Immunology
Annual Review of Cell and Developmental Biology 40, 283 (2024); https://doi.org/10.1146/annurev-cellbio-112122-023316
/content/journals/10.1146/annurev-cellbio-112122-023316
/content/journals/10.1146/annurev-cellbio-112122-023316
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