Bioengineering thymus organoids to restore thymic function and induce donor-specific immune tolerance to allografts

Molecular Therapy

Volumn 23, Issue 7, 2015, Pages 1262-1277

  Fan, Yong ^a   Tajima, Asako ^a   Goh, Saik Kia ^b   Geng, Xuehui ^c   Gualtierotti, Giulio ^c   Grupillo, Maria ^c   Coppola, Antonina ^c,d   Bertera, Suzanne ^a   Rudert, William A ^a   Banerjee, Ipsita ^b   Bottino, Rita ^a   Trucco, Massimo ^a  

^a ALLEGHENY HEALTH NETWORK   (United States)

^b University of Pittsburgh   (United States)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF PALERMO   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

OVALBUMIN;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BANDAGE; CELL CULTURE; CELL ISOLATION; CELL POPULATION; CELL SURVIVAL; CELLULAR IMMUNITY; CONTROLLED STUDY; EPITHELIUM CELL; GAUZE DRESSING; GRAFT RECIPIENT; GRAFT REJECTION; HISTOCOMPATIBILITY; IMMUNOLOGICAL TOLERANCE; IN VIVO STUDY; MOUSE; NONHUMAN; ORGAN DONOR; SKIN ALLOGRAFT; SUTURE; T LYMPHOCYTE; THYMUS; THYMUS FUNCTION; THYMUS TRANSPLANTATION; TISSUE ENGINEERING; TISSUE REPAIR; ALLOGRAFT; ALLOTRANSPLANTATION; ANIMAL; BIOENGINEERING; CYTOLOGY; CYTOPLASM; GROWTH, DEVELOPMENT AND AGING; IMMUNOLOGY; REGENERATIVE MEDICINE;

MUS MUSCULUS;

ALLOGRAFTS; ANIMALS; BIOENGINEERING; EPITHELIAL CELLS; IMMUNE TOLERANCE; MICE; ORGANOIDS; REGENERATIVE MEDICINE; THYMUS GLAND; TRANSPLANTATION, HOMOLOGOUS;

EID: 84934436044     PISSN: 15250016     EISSN: 15250024     Source Type: Journal    
DOI: 10.1038/mt.2015.77     Document Type: Article

References (71)

1. Fink, PJ (2013). The biology of recent thymic emigrants. Annu Rev Immunol 31: 31-50.
2. Boehm, T (2008). Thymus development and function. Curr Opin Immunol 20: 178-184.
3. Heng, TS, Chidgey, AP and Boyd, RL (2010). Getting back at nature: understanding thymic development and overcoming its atrophy. Curr Opin Pharmacol 10: 425-433.
4. Fletcher, AL, Calder, A, Hince, MN, Boyd, RL and Chidgey, AP (2011). The contribution of thymic stromal abnormalities to autoimmune disease. Crit Rev Immunol 31: 171-187.
5. Takada, K, Ohigashi, I, Kasai, M, Nakase, H and Takahama, Y (2014). Development and function of cortical thymic epithelial cells. Curr Top Microbiol Immunol 373: 1-17.
6. Anderson, G and Takahama, Y (2012). Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33: 256-263.
7. Gill, J, Malin, M, Hollander, GA and Boyd, R (2002). Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 3: 635-642.
8. Bennett, AR, Farley, A, Blair, NF, Gordon, J, Sharp, L and Blackburn, CC (2002). Identification and characterization of thymic epithelial progenitor cells. Immunity 16: 803-814.
9. Nitta, T, Ohigashi, I, Nakagawa, Y and Takahama, Y (2011). Cytokine crosstalk for thymic medulla formation. Curr Opin Immunol 23: 190-197.
10. Zartman, JJ and Shvartsman, SY (2010). Unit operations of tissue development: epithelial folding. Annu Rev Chem Biomol Eng 1: 231-246.
11. van Ewijk, W, Wang, B, Hollander, G, Kawamoto, H, Spanopoulou, E, Itoi, M et al. (1999). Thymic microenvironments, 3-D versus 2-D?. Semin Immunol 11: 57-64.
12. Calderon, L and Boehm, T (2012). Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell 149: 159-172.
13. Bonfanti, P, Claudinot, S, Amici, AW, Farley, A, Blackburn, CC and Barrandon, Y (2010). Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466: 978-982.
14. Flomerfelt, FA, El Kassar, N, Gurunathan, C, Chua, KS, League, SC, Schmitz, S et al. (2010). Tbata modulates thymic stromal cell proliferation and thymus function. J Exp Med 207: 2521-2532.
15. Marshall, D, Bagley, J, Le, P, Hogquist, K, Cyr, S, Von Schild, E et al. (2003). T cell generation including positive and negative selection ex vivo in a three-dimensional matrix. J Hematother Stem Cell Res 12: 565-574.
16. Anderson, KL, Moore, NC, McLoughlin, DE, Jenkinson, EJ and Owen, JJ (1998). Studies on thymic epithelial cells in vitro. Dev Comp Immunol 22: 367-377.
17. Pinto, S, Schmidt, K, Egle, S, Stark, HJ, Boukamp, P and Kyewski, B (2013). An organotypic coculture model supporting proliferation and differentiation of medullary thymic epithelial cells and promiscuous gene expression. J Immunol 190: 1085-1093.
18. Chung, B, Montel-Hagen, A, Ge, S, Blumberg, G, Kim, K, Klein, S et al. (2014). Engineering the human thymic microenvironment to support thymopoiesis in vivo. Stem Cells 32: 2386-2396.
19. Orlando, G, Soker, S and Stratta, RJ (2013). Organ bioengineering and regeneration as the new Holy Grail for organ transplantation. Ann Surg 258: 221-232.
20. Gilbert, TW, Sellaro, TL and Badylak, SF (2006). Decellularization of tissues and organs. Biomaterials 27: 3675-3683.
21. Ott, HC, Matthiesen, TS, Goh, SK, Black, LD, Kren, SM, Netoff, TI et al. (2008). Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat Med 14: 213-221.
22. Goh, SK, Bertera, S, Olsen, P, Candiello, JE, Halfter, W, Uechi, G et al. (2013). Perfusion-decellularized pancreas as a natural 3D scaffold for pancreatic tissue and whole organ engineering. Biomaterials 34: 6760-6772.
23. Shin'oka, T, Imai, Y and Ikada, Y (2001). Transplantation of a tissue-engineered pulmonary artery. N Engl J Med 344: 532-533.
24. Schechner, JS, Crane, SK, Wang, F, Szeglin, AM, Tellides, G, Lorber, MI et al. (2003). Engraftment of a vascularized human skin equivalent. FASEB J 17: 2250-2256.
25. Sjoqvist, S, Jungebluth, P, Lim, ML, Haag, JC, Gustafsson, Y, Lemon, G et al. (2014). Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats. Nat Commun 5: 3562.
26. Ott, HC, Clippinger, B, Conrad, C, Schuetz, C, Pomerantseva, I, Ikonomou, L et al. (2010). Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16: 927-933.
27. Song, JJ, Guyette, JP, Gilpin, SE, Gonzalez, G, Vacanti, JP and Ott, HC (2013). Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med 19: 646-651.
28. Uygun, BE, Soto-Gutierrez, A, Yagi, H, Izamis, ML, Guzzardi, MA, Shulman, C et al. (2010). Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16: 814-820.
29. Petersen, TH, Calle, EA, Zhao, L, Lee, EJ, Gui, L, Raredon, MB et al. (2010). Tissue-engineered lungs for in vivo implantation. Science 329: 538-541.
30. Macchiarini, P, Jungebluth, P, Go, T, Asnaghi, MA, Rees, LE, Cogan, TA et al. (2008). Clinical transplantation of a tissue-engineered airway. Lancet 372: 2023-2030.
31. Goh, SK, Olsen, P and Banerjee, I (2013). Extracellular matrix aggregates from differentiating embryoid bodies as a scaffold to support ESC proliferation and differentiation. PLoS One 8: e61856.
32. Fan, Y, Rudert, WA, Grupillo, M, He, J, Sisino, G and Trucco, M (2009). Thymusspecific deletion of insulin induces autoimmune diabetes. EMBO J 28: 2812-2824.
33. Bleul, CC, Corbeaux, T, Reuter, A, Fisch, P, Monting, JS and Boehm, T (2006). Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441: 992-996.
34. Corbeaux, T, Hess, I, Swann, JB, Kanzler, B, Haas-Assenbaum, A and Boehm, T (2010). Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc Natl Acad Sci USA 107: 16613-16618.
35. Klein, L, Hinterberger, M, Wirnsberger, G and Kyewski, B (2009). Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9: 833-844.
36. Mathis, D and Benoist, C (2009). Aire. Annu Rev Immunol 27: 287-312.
37. Bonner, SM, Pietropaolo, SL, Fan, Y, Chang, Y, Sethupathy, P, Morran, MP et al. (2012). Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. J Biol Chem 287: 17882-17893.
38. Depreter, MG, Blair, NF, Gaskell, TL, Nowell, CS, Davern, K, Pagliocca, A et al. (2008). Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc Natl Acad Sci USA 105: 961-966.
39. Manley, NR, Richie, ER, Blackburn, CC, Condie, BG and Sage, J (2011). Structure and function of the thymic microenvironment. Front Biosci (Landmark Ed) 16: 2461-2477.
40. Wong, K, Lister, NL, Barsanti, M, Lim, JM, Hammett, MV, Khong, DM et al. (2014). Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep 8: 1198-1209.
41. Foss, DL, Donskoy, E and Goldschneider, I (2001) The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J Exp Med 193: 365-374.
42. De Barros, SC, Zimmermann, VS and Taylor, N (2013). Concise review: hematopoietic stem cell transplantation: targeting the thymus. Stem Cells 31: 1245-1251.
43. Krell, PF, Reuther, S, Fischer, U, Keller, T, Weber, S, Gombert, M et al. (2013). Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a chain CDR3 sequence associated with hepatitis-induced pathogenesis. Haematologica 98: 1388-1396.
44. Min, B and Paul, WE (2005). Endogenous proliferation: burst-like CD4 T cell proliferation in lymphopenic settings. Semin Immunol 17: 201-207.
45. Thornton, AM, Korty, PE, Tran, DQ, Wohlfert, EA, Murray, PE, Belkaid, Y et al. (2010). Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184: 3433-3441.
46. Rae, M (2013). First Glimpse of Thymic Rejuvenation. Vol. 2013. http://sens.org/ research/research-blog/first-glimpse-Thymic-rejuvenation.
47. Falcon, J (2013). Techniques for thymic decellularization. J Immunol 190: 135.28.
48. Komori, J, Boone, L, DeWard, A, Hoppo, T and Lagasse, E (2012). The mouse lymph node as an ectopic transplantation site for multiple tissues. Nat Biotechnol 30: 976-983.
49. Posselt, AM, Barker, CF, Tomaszewski, JE, Markmann, JF, Choti, MA and Naji, A (1990). Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science 249: 1293-1295.
50. Gottrand, G, Taleb, K, Ragon, I, Bergot, AS, Goldstein, JD and Marodon, G (2012). Intrathymic injection of lentiviral vector curtails the immune response in the periphery of normal mice. J Gene Med 14: 90-99.
51. Wekerle, T and Sykes, M (2001). Mixed chimerism and transplantation tolerance. Annu Rev Med 52: 353-370.
52. Chu, Q, Moreland, RJ, Gao, L, Taylor, KM, Meyers, E, Cheng, SH et al. (2010). Induction of immune tolerance to a therapeutic protein by intrathymic gene delivery. Mol Ther 18: 2146-2154.
53. Poznansky, MC, Evans, RH, Foxall, RB, Olszak, IT, Piascik, AH, Hartman, KE et al. (2000). Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat Biotechnol 18: 729-734.
54. Seach, N, Mattesich, M, Abberton, K, Matsuda, K, Tilkorn, DJ, Rophael, J et al. (2010). Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng Part C Methods 16: 543-551.
55. Alpdogan, O, Hubbard, VM, Smith, OM, Patel, N, Lu, S, Goldberg, GL et al. (2006). Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 107: 2453-2460.
56. Erickson, M, Morkowski, S, Lehar, S, Gillard, G, Beers, C, Dooley, J et al. (2002). Regulation of thymic epithelium by keratinocyte growth factor. Blood 100: 3269-3278.
57. Kermani, H, Goffinet, L, Mottet, M, Bodart, G, Morrhaye, G, Dardenne, O et al. (2012). Expression of the growth hormone/insulin-like growth factor axis during Balb/c thymus ontogeny and effects of growth hormone upon ex vivo T cell differentiation. Neuroimmunomodulation 19: 137-147.
58. Dudakov, JA, Hanash, AM, Jenq, RR, Young, LF, Ghosh, A, Singer, NV et al. (2012). Interleukin-22 drives endogenous thymic regeneration in mice. Science 336: 91-95.
59. Bredenkamp, N, Nowell, CS and Blackburn, CC (2014). Regeneration of the aged thymus by a single transcription factor. Development 141: 1627-1637.
60. Jin, X, Nowell, CS, Ulyanchenko, S, Stenhouse, FH and Blackburn, CC (2014). Long-Term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression. PLoS One 9: e114842.
61. Sun, X, Xu, J, Lu, H, Liu, W, Miao, Z, Sui, X et al. (2013). Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13: 230-236.
62. Parent, AV, Russ, HA, Khan, IS, LaFlam, TN, Metzger, TC, Anderson, MS et al. (2013). Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13: 219-229.
63. Inami, Y, Yoshikai, T, Ito, S, Nishio, N, Suzuki, H, Sakurai, H et al. (2011). Differentiation of induced pluripotent stem cells to thymic epithelial cells by phenotype. Immunol Cell Biol 89: 314-321.
64. Bredenkamp, N, Ulyanchenko, S, O'Neill, KE, Manley, NR, Vaidya, HJ and Blackburn, CC (2014). An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol 16: 902-908.
65. Hsu, PD, Lander, ES and Zhang, F (2014). Development and applications of CRISPRCas9 for genome engineering. Cell 157: 1262-1278.
66. Mali, P, Yang, L, Esvelt, KM, Aach, J, Guell, M, DiCarlo, JE et al. (2013). RNA-guided human genome engineering via Cas9. Science 339: 823-826.
67. Seach, N, Wong, K, Hammett, M, Boyd, RL and Chidgey, AP (2012). Purified enzymes improve isolation and characterization of the adult thymic epithelium. J Immunol Methods 385: 23-34.
68. Quah, BJ and Parish, CR (2012). New and improved methods for measuring lymphocyte proliferation in vitro and in vivo using CFSE-like fluorescent dyes. J Immunol Methods 379: 1-14.
69. Hogquist, KA (2001). Assays of thymic selection. Fetal thymus organ culture and in vitro thymocyte dulling assay. Methods Mol Biol 156: 219-232.
70. Fan, Y, Gualtierotti, G, Tajima, A, Grupillo, M, Coppola, A, He, J et al. (2014). Compromised central tolerance of ICA69 induces multiple organ autoimmunity. J Autoimmun 53: 10-25.
71. Fan, Y, Menon, RK, Cohen, P, Hwang, D, Clemens, T, DiGirolamo, DJ et al. (2009). Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem 284: 19937-19944.