Construction of a functional thymic microenvironment from pluripotent stem cells for the induction of central tolerance

Regenerative Medicine

Volumn 10, Issue 3, 2015, Pages 317-329

  Bredenkamp, Nicholas ^a,b   Jin, Xin ^a,c   Liu, Dong ^a   O'neill, Kathy E ^a   Manley, Nancy R ^c   Blackburn, Catherine Clare ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^c Beijing Jing Meng Stem Cell Technology Co   (China)

Author keywords

direct reprogramming; directed differentiation; microenvironment; pluripotent stem cell; progenitor cell; stem cell; thymic epithelial cell; thymus

Indexed keywords

MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; T LYMPHOCYTE RECEPTOR BETA CHAIN;

CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL LINEAGE; CELL MIGRATION; EMBRYONIC STEM CELL; ENDODERM; EPITHELIUM CELL; HUMAN; IMMUNOLOGICAL TOLERANCE; NONHUMAN; NUCLEAR REPROGRAMMING; ORGANOGENESIS; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PURIFYING SELECTION; REVIEW; THYMIC EPITHELIAL CELL; THYMOCYTE; THYMUS; THYMUS FUNCTION; THYMUS TRANSPLANTATION; ANIMAL; CYTOLOGY; CYTOPLASM; IMMUNOLOGY; STEM CELL NICHE; TRANSPLANTATION;

ANIMALS; CELLULAR REPROGRAMMING; HUMANS; IMMUNE TOLERANCE; ORGANOIDS; PLURIPOTENT STEM CELLS; STEM CELL NICHE; THYMUS GLAND;

EID: 84929996950     PISSN: 17460751     EISSN: 1746076X     Source Type: Journal    
DOI: 10.2217/rme.15.8     Document Type: Review

References (131)

1. Miller JFAP. Immunological function of the thymus. Lancet 2, 748-749 (1961).
2. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14(6), 377-391 (2014).
3. Anderson G, Takahama Y. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 33(6), 256-263 (2012).
4. Koch U, Radtke F. Mechanisms of T cell development and transformation. Annu. Rev. Cell Dev. Biol. 27, 539-562 (2011).
5. Flanagan SP. 'Nude', a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8, 295 (1966).
6. Markert ML, Boeck A, Hale LP et al. Transplantation of thymus tissue in complete DiGeorge syndrome. N. Engl. J. Med. 341, 1180-1189 (1999).
7. Frank J, Pignata C, Panteleyev AA et al. Exposing the human nude phenotype [letter]. Nature 398(6727), 473-474 (1999).
8. Villasenor J, Benoist C, Mathis D. AIRE and APECED: molecular insights into an autoimmune disease. Immunol. Rev. 204, 156-164 (2005).
9. Chinn IK, Blackburn CC, Manley NR, Sempowski GD. Changes in primary lymphoid organs with aging. Semin. Immunol. 24(5), 309-320 (2012).
10. Weng NP. Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24(5), 495-499 (2006).
11. Lynch HE, Goldberg GL, Chidgey A, Van Den Brink MR, Boyd R, Sempowski GD. Thymic involution and immune reconstitution. Trends Immunol. 30(7), 366-373 (2009).
12. Nikolich-Zugich J, Rudd BD. Immune memory and aging: an infinite or finite resource? Curr. Opin. Immunol. 22(4), 535-540 (2010).
13. Holland AM, Van Den Brink MR. Rejuvenation of the aging T cell compartment. Curr. Opin. Immunol. 21(4), 454-459 (2009).
14. Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu. Rev. Immunol. 18, 529-560 (2000).
15. Fairchild PJ. The challenge of immunogenicity in the quest for induced pluripotency. Nat. Rev. Immunol. 10(12), 868-875 (2010).
16. Van Den Brink MR, Alpdogan O, Boyd RL. Strategies to enhance T-cell reconstitution in immunocompromised patients. Nat. Rev. Immunol. 4(11), 856-867 (2004).
17. Markert ML, Marques JG, Neven B et al. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID). A report of 2 cases. Blood 117(2), 688-696 (2011).
18. Markert ML, Devlin BH, Chinn IK, Mccarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol. Res. 44(1-3), 61-70 (2009).
19. Smith A. A glossary for stem-cell biology. Nature 441, 1060(206).doi:10.1038/nature04954 (2006).
20. Petrie HT, Zuniga-Pflucker JC. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649-679 (2007).
21. Bhandoola A, Von Boehmer H, Petrie HT, Zuniga-Pflucker JC. Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from. Immunity 26(6), 678-689 (2007).
22. Lind EF, Prockop SE, Porritt HE, Petrie HT. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194(2), 127-134 (2001).
23. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531-564 (2012).
24. Petrie HT. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol. Rev. 189(1), 8-20 (2002).
25. Ehrlich LI, Oh DY, Weissman IL, Lewis RS. Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. Immunity 31(6), 986-998 (2009).
26. Boyd RL, Tucek CL, Godfrey DI et al. The thymic microenvironment. Immunol. Today 14(9), 445-459 (1993).
27. Fend F, Nachbaur D, Oberwasserlechner F, Kreczy A, Huber H, Muller-Hermelink HK. Phenotype and topography of human thymic B cells. An immunohistologic study. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 60(6), 381-388 (1991).
28. Manley NR, Richie ER, Blackburn CC, Condie BG, Sage J. Structure and function of the thymic microenvironment. Front. Biosci. (Landmark Ed.) 16, 2461-2477 (2011).
29. Nowell CS, Bredenkamp N, Tetelin S et al. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLoS Genet. 7(11), e1002348 (2011).
30. Chen L, Xiao S, Manley NR. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosagesensitive manner. Blood 113(3), 567-574 (2009).
31. Zuklys S, Mayer CE, Zhanybekova S et al. MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J. Immunol. 189(8), 3894-3904 (2012).
32. Van Ewijk W, Wang B, Hollander G et al. Thymic microenvironments, 3-D versus 2-D? Semin. Immunol. 11(1), 57-64 (1999).
33. Mohtashami M, Zuniga-Pflucker JC. Three-dimensional architecture of the thymus is required to maintain deltalike expression necessary for inducing T cell development. J. Immunol. 176(2), 730-734 (2006).
34. Zlotoff DA, Bhandoola A. Hematopoietic progenitor migration to the adult thymus. Ann. NY Acad. Sci. 1217, 122-138 (2011).
35. Gray DH, Seach N, Ueno T et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108(12), 3777-3785 (2006).
36. Hozumi K, Mailhos C, Negishi N et al. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205(11), 2507-2513 (2008).
37. Billiard F, Kirshner JR, Tait M et al. Ongoing Dll4-Notch signaling is required for T-cell homeostasis in the adult thymus. Eur. J. Immunol. 41(8), 2207-2216 (2011).
38. Koch U, Fiorini E, Benedito R et al. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205(11), 2515-2523 (2008).
39. Fiorini E, Ferrero I, Merck E et al. Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J. Immunol. 181(12), 8199-8203 (2008).
40. Moore TA, Zlotnik A. T-cell lineage commitment and cytokine responses of thymic progenitors. Blood 86(5), 1850-1860 (1995).
41. Godfrey DI, Zlotnik A, Suda T. Phenotypic and functional characterization of c-kit expression during intrathymic T cell development. J. Immunol. 149(7), 2281-2285 (1992).
42. Benz C, Heinzel K, Bleul CC. Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 34(12), 3652-3663 (2004).
43. Uehara S, Hayes SM, Li L et al. Premature expression of chemokine receptor CCR9 impairs T cell development. J. Immunol. 176(1), 75-84 (2006).
44. Janas ML, Turner M. Stromal cell-derived factor 1alpha and CXCR4: newly defined requirements for efficient thymic beta-selection. Trends Immunol. 31(10), 370-376 (2010).
45. Murata S, Takahama Y, Tanaka K. Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. 20(2), 192-196 (2008).
46. Nitta T, Murata S, Sasaki K et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32(1), 29-40 (2010).
47. Takahama Y, Takada K, Murata S, Tanaka K. Beta5tcontaining thymoproteasome: specific expression in thymic cortical epithelial cells and role in positive selection of CD8+ T cells. Curr. Opin. Immunol. 24(1), 92-98 (2012).
48. Ueno T, Saito F, Gray DH et al. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200(4), 493-505 (2004).
49. Lkhagvasuren E, Sakata M, Ohigashi I, Takahama Y. Lymphotoxin beta receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells. J. Immunol. 190(10), 5110-5117 (2013).
50. Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat. Rev. Immunol. 6(2), 127-135 (2006).
51. Sprent J, Gao EK, Webb SR. T cell reactivity to MHC molecules: immunity versus tolerance. Science 248(4961), 1357-1363 (1990).
52. Kyewski BA, Fathman CG, Rouse RV. Intrathymic presentation of circulating non-MHC antigens by medullary dendritic cells. An antigen-dependent microenvironment for T cell differentiation. J. Exp. Med. 163(2), 231-246 (1986).
53. Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298(5597), 1395-1401 (2002).
54. Kyewski B, Derbinski J. Self-representation in the thymus: an extended view. Nat. Rev. Immunol. 4(9), 688-698 (2004).
55. Mathis D, Benoist C. Aire. Annu. Rev. Immunol. 27, 287-312 (2009).
56. Abramson J, Giraud M, Benoist C, Mathis D. Aire's partners in the molecular control of immunological tolerance. Cell 140(1), 123-135 (2010).
57. Keane P, Ceredig R, Seoighe C. Promiscuous mRNA splicing under the control of AIRE in medullary thymic epithelial cells. Bioinformatics pii: btu785 (2014).
58. Sansom SN, Shikama-Dorn N, Zhanybekova S et al. 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(12), 1918-1931 (2014).
59. Boehm T, Scheu S, Pfeffer K, Bleul CC. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J. Exp. Med. 198(5), 757-769 (2003).
60. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22(3), 329-341 (2005).
61. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30(5), 616-625 (2009).
62. Farley AM, Morris LX, Vroegindeweij E et al. Dynamics of thymus organogenesis and colonization in early human development. Development 140(9), 2015-2026 (2013).
63. Gordon J, Wilson VA, Blair NF et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nat. Immunol. 5, 546-553 (2004).
64. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441(7096), 988-991 (2006).
65. Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441(7096), 992-996 (2006).
66. Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414(6865), 763-768 (2001).
67. Hamazaki Y, Fujita H, Kobayashi T et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat. Immunol. 8(3), 304-311 (2007).
68. Shakib S, Desanti GE, Jenkinson WE, Parnell SM, Jenkinson EJ, Anderson G. Checkpoints in the development of thymic cortical epithelial cells. J. Immunol. 182(1), 130-137 (2009).
69. Klug DB, Carter C, Gimenez-Conti IB, Richie ER. Cutting edge: thymocyte-independent and thymocytedependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169(6), 2842-2845 (2002).
70. Mouri Y, Yano M, Shinzawa M et al. Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J. Immunol. 186(9), 5047-5057 (2011).
71. Akiyama T, Shimo Y, Yanai H et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and selftolerance. Immunity 29(3), 423-437 (2008).
72. Hikosaka Y, Nitta T, Ohigashi I et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29(3), 438-450 (2008).
73. Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC. Identification and characterization of thymic epithelial progenitor cells. Immunity 16(6), 803-814 (2002).
74. Gill J, Malin M, Hollander GA, Boyd R. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat. Immunol. 3(7), 635-642 (2002).
75. Rossi SW, Chidgey AP, Parnell SM et al. Redefining epithelial progenitor potential in the developing thymus. Eur. J. Immunol. 37(9), 2411-2418 (2007).
76. Auerbach R. Morphogenetic interactions in the development of the mouse thymus gland. Dev. Biol. 2, 271-284 (1960).
77. Blackburn CC, Manley NR. Developing a new paradigm for thymus organogenesis. Nat. Rev. Immunol. 4(4), 278-289 (2004).
78. Manley NR, Condie BG. Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog. Mol. Biol. Transl. Sci. 92, 103-120 (2010).
79. Gordon J, Manley NR. Mechanisms of thymus organogenesis and morphogenesis. Development 138(18), 3865-3878 (2011).
80. Bajoghli B, Aghaallaei N, Hess I et al. Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138(1), 186-197 (2009).
81. Corbeaux T, Hess I, Swann JB, Kanzler B, Haas-Assenbaum A, Boehm T. Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc. Natl Acad. Sci. USA 107(38), 16613-16618 (2010).
82. Zook EC, Krishack PA, Zhang S et al. Overexpression of Foxn1 attenuates age-Associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118(22), 5723-5731 (2011).
83. Calderon L, Boehm T. Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell 149(1), 159-172 (2012).
84. Bredenkamp N, Nowell CS, Blackburn CC. Regeneration of the aged thymus by a single transcription factor. Development 141(8), 1627-1637 (2014).
85. Green MD, Chen A, Nostro MC et al. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat. Biotech. 29(3), 267-272 (2011).
86. Ucar A, Ucar O, Klug P et al. Adult thymus contains FoxN1(-) epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41(2), 257-269 (2014).
87. Jin X, Nowell CS, Ulyanchenko S, Stenhouse FH, Blackburn CC. Long-Term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression. PLoS One 9(12), e114842 (2014).
88. Conlon FL, Lyons KM, Takaesu N et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120(7), 1919-1928 (1994).
89. Iannaccone PM, Zhou X, Khokha M, Boucher D, Kuehn MR. Insertional mutation of a gene involved in growth regulation of the early mouse embryo. Dev. Dyn. 194(3), 198-208 (1992).
90. D'amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotech. 23(12), 1534-1541 (2005).
91. Kubo A, Shinozaki K, Shannon JM et al. Development of definitive endoderm from embryonic stem cells in culture. Development 131(7), 1651-1662 (2004).
92. Yasunaga M, Tada S, Torikai-Nishikawa S et al. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat. Biotech. 23(12), 1542-1550 (2005).
93. Morrison GM, Oikonomopoulou I, Migueles RP et al. Anterior definitive endoderm from ESCs reveals a role for FGF signaling. Cell Stem Cell 3(4), 402-415 (2008).
94. Cheng X, Tiyaboonchai A, Gadue P. Endodermal stem cell populations derived from pluripotent stem cells. Curr. Opin. Cell Biol. 25(2), 265-271 (2013).
95. Hannan NR, Fordham RP, Syed YA et al. Generation of multipotent foregut stem cells from human pluripotent stem cells. Stem Cell Rep. 1(4), 293-306 (2013).
96. Mccracken KW, Cata EM, Crawford CM et al. Modelling human development and disease in pluripotent stem-cellderived gastric organoids. Nature 516(7531), 400-404 (2014).
97. Huang SX, Islam MN, O'neill J et al. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat. Biotech. 32(1), 84-91 (2014).
98. Watson CL, Mahe MM, Munera J et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20(11), 1310-1314 (2014).
99. Wells JM, Spence JR. How to make an intestine. Development 141(4), 752-760 (2014).
100. Forster R, Chiba K, Schaeffer L et al. Human intestinal tissue with adult stem cell properties derived from pluripotent stem cells. Stem Cell Rep. 2(6), 838-852 (2014).
101. Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C. Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J. Immunol. 167(4), 1954-1961 (2001).
102. Lai L, Jin J. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells 27(12), 3012-3020 (2009).
103. Lai L, Cui C, Jin J et al. Mouse embryonic stem cellderived thymic epithelial cell progenitors enhance T-cell reconstitution after allogeneic bone marrow transplantation. Blood 118(12), 3410-3418 (2011).
104. Gonzalez B, Denzel S, Mack B, Conrad M, Gires O. EpCAM is involved in maintenance of the murine embryonic stem cell phenotype. Stem Cells 27(8), 1782-1791 (2009).
105. Inami Y, Yoshikai T, Ito S et al. Differentiation of induced pluripotent stem cells to thymic epithelial cells by phenotype. Immunol. Cell Biol. 89(2), 314-321 (2011).
106. Parent AV, Russ HA, Khan IS et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13(2), 219-229 (2013).
107. Sun X, Xu J, Lu H et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13(2), 230-236 (2013).
108. Soh CL, Giudice A, Jenny RA et al. FOXN1 (GFP/w) reporter hESCs enable identification of integrin-beta4, HLA-DR, and EpCAM as markers of human PSC-derived FOXN1(+) thymic epithelial progenitors. Stem Cell Rep. 2(6), 925-937 (2014).
109. Bonfanti P, Claudinot S, Amici AW, Farley A, Blackburn CC, Barrandon Y. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466(7309), 978-982 (2010).
110. Wong K, Lister NL, Barsanti M et al. Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep. 8(4), 1198-1209 (2014).
111. Weintraub H, Tapscott SJ, Davis RL et al. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc. Natl Acad. Sci. USA 86(14), 5434-5438 (1989).
112. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4), 663-676 (2006).
113. Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5), 861-872 (2007).
114. Laiosa CV, Stadtfeld M, Xie H, De Andres-Aguayo L, Graf T. Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity 25(5), 731-744 (2006).
115. Szabo E, Rampalli S, Risueno RM et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468(7323), 521-526 (2010).
116. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284), 1035-1041 (2010).
117. Pang ZP, Yang N, Vierbuchen T et al. Induction of human neuronal cells by defined transcription factors. Nature 476(7359), 220-223 (2011).
118. Efe JA, Hilcove S, Kim J et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat. Cell Biol. 13(3), 215-222 (2011).
119. Ieda M, Fu JD, Delgado-Olguin P et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142(3), 375-386 (2010).
120. Huang P, He Z, Ji S et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475(7356), 386-389 (2011).
121. Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475(7356), 390-393 (2011).
122. Bredenkamp N, Ulyanchenko S, O'neill KE, Manley NR, Vaidya HJ, Blackburn CC. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat. Cell Biol. 16(9), 902-908 (2014).
123. Dudakov JA, Hanash AM, Jenq RR et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336(6077), 91-95 (2012).
124. Godfrey DI, Kennedy J, Suda T, Zlotnik A. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8-Triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150(10), 4244-4252 (1993).
125. Petrie HT. Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nat. Rev. Immunol. 3(11), 859-866 (2003).
126. Porritt HE, Rumfelt LL, Tabrizifard S, Schmitt TM, Zuniga-Pflucker JC, Petrie HT. Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity 20(6), 735-745 (2004).
127. Allman D, Sambandam A, Kim S et al. Thymopoiesis independent of common lymphoid progenitors. Nat. Immunol. 4(2), 168-174 (2003).
128. Adolfsson J, Mansson R, Buza-Vidas N et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythromegakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121(2), 295-306 (2005).
129. Sambandam A, Maillard I, Zediak VP et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat. Immunol. 6(7), 663-670 (2005).
130. Galy A, Verma S, Barcena A, Spits H. Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development. J. Exp. Med. 178(2), 391-401 (1993).
131. Haddad R, Guimiot F, Six E et al. Dynamics of thymuscolonizing cells during human development. Immunity 24(2), 217-230 (2006).