Biomaterials Research (생체재료학회지)

Korean Society for Biomaterials (한국생체재료학회)
권호 표지
DOI QR코드

DOI QR Code

Engineering approaches for regeneration of T lymphopoiesis

  • Roh, Kyung-Ho (The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University) ;
  • Roy, Krishnendu (The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University)
  • Received : 2016.03.22
  • Accepted : 2016.06.13
  • Published : 2016.09.01
⟨ Previous Next ⟩

Abstract

T cells play a central role in immune-homeostasis; specifically in the induction of antigen-specific adaptive immunity against pathogens and mutated self with immunological memory. The thymus is the unique organ where T cells are generated. In this review, first the complex structures and functions of various thymic microcompartments are briefly discussed to identify critical engineering targets for regeneration of thymic functions in vitro and in vivo. Then the biomimetic regenerative engineering approaches are reviewed in three categories: 1) reconstruction of 3-D thymic architecture, 2) cellular engineering, and 3) biomaterials-based artificial presentation of critical biomolecules. For each engineering approach, remaining challenges and clinical opportunities are also identified and discussed.

Keywords

Acknowledgement

Supported by : NIST

References

  1. Miller JF. The discovery of thymus function and of thymus-derived lymphocytes. Immunol Rev. 2002;185:7-14. https://doi.org/10.1034/j.1600-065X.2002.18502.x
  2. Petrie HT. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol Rev. 2002;189:8-19. https://doi.org/10.1034/j.1600-065X.2002.18902.x
  3. Seach N, Layton D, Lim J, Chidgey A, Boyd R. Thymic generation and regeneration: a new paradigm for establishing clinical tolerance of stem cell-based therapies. Curr Opin Biotechnol. 2007;18(5):441-7. https://doi.org/10.1016/j.copbio.2007.07.001
  4. Gray DH, Ueno T, Chidgey AP, Malin M, Goldberg GL, Takahama Y, Boyd RL. Controlling the thymic microenvironment. Curr Opin Immunol. 2005;17(2):137-43. https://doi.org/10.1016/j.coi.2005.02.001
  5. Ladi E, Yin X, Chtanova T, Robey EA. Thymic microenvironments for T cell differentiation and selection. Nat Immunol. 2006;7(4):338-43. https://doi.org/10.1038/ni1323
  6. Calderon L, Boehm T. Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell. 2012;149(1):159-72. https://doi.org/10.1016/j.cell.2012.01.049
  7. 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. 1993;150(10):4244-52.
  8. Ebert PJ, Li QJ, Huppa JB, Davis MM. Functional development of the T cell receptor for antigen. Prog Mol Biol Transl Sci. 2010;92:65-100.
  9. Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1(1):31-40. https://doi.org/10.1038/35095500
  10. 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. 2003;198(5):757-69. https://doi.org/10.1084/jem.20030794
  11. van Ewijk W, Wang B, Hollander G, Kawamoto H, Spanopoulou E, Itoi M, Amagai T, Jiang YF, Germeraad WT, Chen WF, et al. Thymic microenvironments, 3-D versus 2-D? Semin Immunol. 1999;11(1):57-64. https://doi.org/10.1006/smim.1998.0158
  12. Cowan JE, Jenkinson WE, Anderson G. Thymus medulla fosters generation of natural Treg cells, invariant gammadelta T cells, and invariant NKT cells: what we learn from intrathymic migration. Eur J Immunol. 2015;45(3):652-60. https://doi.org/10.1002/eji.201445108
  13. Dao T, Guo D, Ploss A, Stolzer A, Saylor C, Boursalian TE, Im JS, Sant'Angelo DB. Development of CD1d-restricted NKT cells in the mouse thymus. Eur J Immunol. 2004;34(12):3542-52. https://doi.org/10.1002/eji.200425546
  14. Bendelac A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J Exp Med. 1995;182(6):2091-6. https://doi.org/10.1084/jem.182.6.2091
  15. Shibata K, Yamada H, Nakamura M, Hatano S, Katsuragi Y, Kominami R, Yoshikai Y. IFN-gamma-producing and IL-17-producing gammadelta T cells differentiate at distinct developmental stages in murine fetal thymus. J Immunol. 2014;192(5):2210-8. https://doi.org/10.4049/jimmunol.1302145
  16. Reinhardt A, Ravens S, Fleige H, Haas JD, Oberdorfer L, Lyszkiewicz M, Forster R, Prinz I. CCR7-mediated migration in the thymus controls gammadelta T-cell development. Eur J Immunol. 2014;44(5):1320-9. https://doi.org/10.1002/eji.201344330
  17. Taghon T, Yui MA, Pant R, Diamond RA, Rothenberg EV. Developmental and molecular characterization of emerging beta- and gammadelta-selected pre-T cells in the adult mouse thymus. Immunity. 2006;24(1):53-64. https://doi.org/10.1016/j.immuni.2005.11.012
  18. Prinz I, Sansoni A, Kissenpfennig A, Ardouin L, Malissen M, Malissen B. Visualization of the earliest steps of gammadelta T cell development in the adult thymus. Nat Immunol. 2006;7(9):995-1003. https://doi.org/10.1038/ni1371
  19. Hayes SM, Li L, Love PE. TCR signal strength influences alphabeta/gammadelta lineage fate. Immunity. 2005;22(5):583-93. https://doi.org/10.1016/j.immuni.2005.03.014
  20. Silva-Santos B, Pennington DJ, Hayday AC. Lymphotoxin-mediated regulation of gammadelta cell differentiation by alphabeta T cell progenitors. Science. 2005;307(5711):925-8. https://doi.org/10.1126/science.1103978
  21. Farr AG, Dooley JL, Erickson M. Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation. Immunol Rev. 2002;189:20-7. https://doi.org/10.1034/j.1600-065X.2002.18903.x
  22. Caramalho I, Nunes-Cabaco H, Foxall RB, Sousa AE. Regulatory T-cell development in the human thymus. Front Immunol. 2015;6:395.
  23. Klein L, Jovanovic K. Regulatory T cell lineage commitment in the thymus. Semin Immunol. 2011;23(6):401-9. https://doi.org/10.1016/j.smim.2011.06.003
  24. Henderson AJ, Dorshkind K. In vitro models of B lymphocyte development. Semin Immunol. 1990;2(3):181-7.
  25. Flomerfelt FA, El Kassar N, Gurunathan C, Chua KS, League SC, Schmitz S, Gershon TR, Kapoor V, Yan XY, Schwartz RH, et al. Tbata modulates thymic stromal cell proliferation and thymus function. J Exp Med. 2010;207(11):2521-32. https://doi.org/10.1084/jem.20092759
  26. Bonfanti P, Claudinot S, Amici AW, Farley A, Blackburn CC, Barrandon Y. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature. 2010;466(7309):978-82. https://doi.org/10.1038/nature09269
  27. Kamarck ME, Gottlieb PD. Expression of thymocyte surface alloantigens in the fetal mouse thymus in vivo and in organ culture. J Immunol. 1977;119(2):407-15.
  28. DeLuca D, Mandel TE, Luckenbach GA, Kennedy MM. Tolerance induction by fusion of fetal thymus lobes in organ culture. J Immunol. 1980;124(4):1821-9.
  29. Ceredig R, Jenkinson EJ, MacDonald HR, Owen JJ. Development of cytolytic T lymphocyte precursors in organ-cultured mouse embryonic thymus rudiments. J Exp Med. 1982;155(2):617-22. https://doi.org/10.1084/jem.155.2.617
  30. Jenkinson EJ, Owen JJ. T-cell differentiation in thymus organ cultures. Semin Immunol. 1990;2(1):51-8.
  31. Jenkinson EJ, Franchi LL, Kingston R, Owen JJ. Effect of deoxyguanosine on lymphopoiesis in the developing thymus rudiment in vitro: application in the production of chimeric thymus rudiments. Eur J Immunol. 1982;12(7):583-7. https://doi.org/10.1002/eji.1830120710
  32. McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988;241(4873):1632-9. https://doi.org/10.1126/science.2971269
  33. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118-30. https://doi.org/10.1038/nri2017
  34. Aldrovandi GM, Feuer G, Gao L, Jamieson B, Kristeva M, Chen IS, Zack JA. The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993;363(6431):732-6. https://doi.org/10.1038/363732a0
  35. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12(11):1316-22. https://doi.org/10.1038/nm1431
  36. Seach N, Mattesich M, Abberton K, Matsuda K, Tilkorn DJ, Rophael J, Boyd RL, Morrison WA. Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng Part CMe. 2010;16(3):543-51. https://doi.org/10.1089/ten.tec.2009.0135
  37. White A, Jenkinson E, Anderson G. Reaggregate thymus cultures. J Vis Exp. 2008;(18): e905.
  38. Anderson G, Jenkinson EJ. Fetal thymus organ culture. CSH Protoc. 2007;2007:pdb prot4808.
  39. Chung B, Montel-Hagen A, Ge S, Blumberg G, Kim K, Klein S, Zhu Y, Parekh C, Balamurugan A, Yang OO, et al. Engineering the human thymic microenvironment to support thymopoiesis in vivo. Stem Cells. 2014;32(9):2386-96. https://doi.org/10.1002/stem.1731
  40. Marshall D, Bagley J, Le P, Hogquist K, Cyr S, Von Schild E, Pykett M, Rosenzweig M. T cell generation including positive and negative selection ex vivo in a three-dimensional matrix. J Hematother Stem Cell Res. 2003;12(5):565-74. https://doi.org/10.1089/152581603322448277
  41. Poznansky MC, Evans RH, Foxall RB, Olszak IT, Piascik AH, Hartman KE, Brander C, Meyer TH, Pykett MJ, Chabner KT, et al. Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat Biotechnol. 2000;18(7):729-34. https://doi.org/10.1038/77288
  42. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571-606. https://doi.org/10.1146/annurev.immunol.23.021704.115601
  43. Kont V, Laan M, Kisand K, Merits A, Scott HS, Peterson P. Modulation of Aire regulates the expression of tissue-restricted antigens. Mol Immunol. 2008;45(1):25-33. https://doi.org/10.1016/j.molimm.2007.05.014
  44. Pinto S, Schmidt K, Egle S, Stark HJ, Boukamp P, Kyewski B. An organotypic coculture model supporting proliferation and differentiation of medullary thymic epithelial cells and promiscuous gene expression. J Immunol. 2013;190(3):1085-93. https://doi.org/10.4049/jimmunol.1201843
  45. Fan Y, Tajima A, Goh SK, Geng X, Gualtierotti G, Grupillo M, Coppola A, Bertera S, Rudert WA, Banerjee I, et al. Bioengineering thymus organoids to restore thymic function and induce donor-specific immune tolerance to allografts. Mol Ther. 2015;23(7):1262-77. https://doi.org/10.1038/mt.2015.77
  46. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat Med. 2008;14(2):213-21. https://doi.org/10.1038/nm1684
  47. Gilbert TW, Sellaro TL, Badylak SF. Decellularization of tissues and organs. Biomaterials. 2006;27(19):3675-83. https://doi.org/10.1016/j.biomaterials.2006.02.014
  48. Orlando G, Soker S, Stratta RJ. Organ bioengineering and regeneration as the new Holy Grail for organ transplantation. Ann Surg. 2013;258(2):221-32. https://doi.org/10.1097/SLA.0b013e31829c79cf
  49. 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. 2014;16(9):902-8. https://doi.org/10.1038/ncb3023
  50. Lai L, Jin J. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells. 2009;27(12):3012-20.
  51. Lai L, Cui C, Jin J, Hao Z, Zheng Q, Ying M, Boyd R, Zhao Y. Mouse embryonic stem cell-derived thymic epithelial cell progenitors enhance Tcell reconstitution after allogeneic bone marrow transplantation. Blood. 2011;118(12):3410-8. https://doi.org/10.1182/blood-2011-03-340794
  52. Inami Y, Yoshikai T, Ito S, Nishio N, Suzuki H, Sakurai H, Isobe K. Differentiation of induced pluripotent stem cells to thymic epithelial cells by phenotype. Immunol Cell Biol. 2011;89(2):314-21. https://doi.org/10.1038/icb.2010.96
  53. Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC, Anderson MS, Hebrok M. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell. 2013;13(2):219-29. https://doi.org/10.1016/j.stem.2013.04.004
  54. Sun XN, Xu J, Lu HX, Liu W, Miao ZC, Sui X, Liu HS, Su L, Du WC, He QH, et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell. 2013;13(2):230-6. https://doi.org/10.1016/j.stem.2013.06.014
  55. Kodama H, Nose M, Niida S, Nishikawa S, Nishikawa S. Involvement of the ckit receptor in the adhesion of hematopoietic stem cells to stromal cells. Exp Hematol. 1994;22(10):979-84.
  56. Nakano T, Kodama H, Honjo T. Generation of lymphohematopoietic cells from embryonic stem cells in culture. Science. 1994;265(5175):1098-101. https://doi.org/10.1126/science.8066449
  57. Pear WS, Radtke F. Notch signaling in lymphopoiesis. Semin Immunol. 2003;15(2):69-79. https://doi.org/10.1016/S1044-5323(03)00003-4
  58. Karanu FN, Murdoch B, Miyabayashi T, Ohno M, Koremoto M, Gallacher L, Wu D, Itoh A, Sakano S, Bhatia M. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood. 2001;97(7):1960-7. https://doi.org/10.1182/blood.V97.7.1960
  59. Schmitt TM, Zuniga-Pflucker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity. 2002;17(6):749-56. https://doi.org/10.1016/S1074-7613(02)00474-0
  60. Zuniga-Pflucker JC. T-cell development made simple. Nat Rev Immunol. 2004;4(1):67-72. https://doi.org/10.1038/nri1257
  61. Mohtashami M, Zuniga-Pflucker JC. Three-dimensional architecture of the thymus is required to maintain delta-like expression necessary for inducing T cell development. J Immunol. 2006;176(2):730-4. https://doi.org/10.4049/jimmunol.176.2.730
  62. de Pooter RF, Cho SK, Carlyle JR, Zuniga-Pflucker JC. In vitro generation of T lymphocytes from embryonic stem cell-derived prehematopoietic progenitors. Blood. 2003;102(5):1649-53. https://doi.org/10.1182/blood-2003-01-0224
  63. Timmermans F, Velghe I, Vanwalleghem L, De Smedt M, Van Coppernolle S, Taghon T, Moore HD, Leclercq G, Langerak AW, Kerre T, et al. Generation of T cells from human embryonic stem cell-derived hematopoietic zones. J Immunol. 2009;182(11):6879-88. https://doi.org/10.4049/jimmunol.0803670
  64. De Smedt M, Hoebeke I, Plum J. Human bone marrow CD34+ progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment. Blood Cells Mol Dis. 2004;33(3):227-32. https://doi.org/10.1016/j.bcmd.2004.08.007
  65. Awong G, Herer E, La Motte-Mohs RN, Zuniga-Pflucker JC. Human CD8 T cells generated in vitro from hematopoietic stem cells are functionally mature. BMC Immunol. 2011;12:22. https://doi.org/10.1186/1471-2172-12-22
  66. Van Coppernolle S, Verstichel G, Timmermans F, Velghe I, Vermijlen D, De Smedt M, Leclercq G, Plum J, Taghon T, Vandekerckhove B, et al. Functionally mature CD4 and CD8 TCRalphabeta cells are generated in OP9-DL1 cultures from human CD34+ hematopoietic cells. J Immunol. 2009;183(8):4859-70. https://doi.org/10.4049/jimmunol.0900714
  67. Zakrzewski JL, Kochman AA, Lu SX, Terwey TH, Kim TD, Hubbard VM, Muriglan SJ, Suh D, Smith OM, Grubin J, et al. Adoptive transfer of Tcell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med. 2006;12(9):1039-47. https://doi.org/10.1038/nm1463
  68. Zhao Y, Parkhurst MR, Zheng Z, Cohen CJ, Riley JP, Gattinoni L, Restifo NP, Rosenberg SA, Morgan RA. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res. 2007;67(6):2425-9. https://doi.org/10.1158/0008-5472.CAN-06-3977
  69. van Lent AU, Nagasawa M, van Loenen MM, Schotte R, Schumacher TN, Heemskerk MH, Spits H, Legrand N. Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors. J Immunol. 2007;179(8):4959-68. https://doi.org/10.4049/jimmunol.179.8.4959
  70. Beaudette-Zlatanova BC, Knight KL, Zhang S, Stiff PJ, Zuniga-Pflucker JC, Le PT. A human thymic epithelial cell culture system for the promotion of lymphopoiesis from hematopoietic stem cells. Exp Hematol. 2011;39(5):570-9. https://doi.org/10.1016/j.exphem.2011.01.014
  71. Clark RA, Yamanaka K, Bai M, Dowgiert R, Kupper TS. Human skin cells support thymus-independent T cell development. J Clin Invest. 2005;115(11):3239-49. https://doi.org/10.1172/JCI24731
  72. Meek B, Van Elssen CH, Huijskens MJ, van der Stegen SJ, Tonnaer S, Lumeij SB, Vanderlocht J, Kirkland MA, Hesselink R, Germeraad WT, et al. T cells fail to develop in the human skin-cell explants system; an inconvenient truth. BMC Immunol. 2011;12:17. https://doi.org/10.1186/1471-2172-12-17
  73. Mohtashami M, Shah DK, Nakase H, Kianizad K, Petrie HT, Zuniga-Pflucker JC. Direct comparison of Dll1- and Dll4-mediated Notch activation levels shows differential lymphomyeloid lineage commitment outcomes. J Immunol. 2010;185(2):867-76. https://doi.org/10.4049/jimmunol.1000782
  74. Varnum-Finney B, Wu L, Yu M, Brashem-Stein C, Staats S, Flowers D, Griffin JD, Bernstein ID. Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. J Cell Sci. 2000;113(Pt 23):4313-8.
  75. Dallas MH, Varnum-Finney B, Delaney C, Kato K, Bernstein ID. Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells. J Exp Med. 2005;201(9):1361-6. https://doi.org/10.1084/jem.20042450
  76. Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood. 2005;106(8):2693-9. https://doi.org/10.1182/blood-2005-03-1131
  77. Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest. 2002;110(8):1165-74. https://doi.org/10.1172/JCI0216167
  78. Dallas MH, Varnum-Finney B, Martin PJ, Bernstein ID. Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. Blood. 2007;109(8):3579-87. https://doi.org/10.1182/blood-2006-08-039842
  79. Taqvi S, Dixit L, Roy K. Biomaterial-based notch signaling for the differentiation of hematopoietic stem cells into T cells. J Biomed Mater Res A. 2006;79(3):689-97.
  80. Lin J, Nie H, Tucker PW, Roy K. Controlled major histocompatibility complex-T cell receptor signaling allows efficient generation of functional, antigenspecific CD8+ T cells from embryonic stem cells and thymic progenitors. Tissue Eng Part A. 2010;16(9):2709-20. https://doi.org/10.1089/ten.tea.2009.0707
  81. Fernandez I, Ooi TP, Roy K. Generation of functional, antigen-specific CD8+ human T cells from cord blood stem cells using exogenous Notch and tetramer-TCR signaling. Stem Cells. 2014;32(1):93-104. https://doi.org/10.1002/stem.1512
  82. Greenberg F. DiGeorge syndrome: an historical review of clinical and cytogenetic features. J Med Genet. 1993;30(10):803-6. https://doi.org/10.1136/jmg.30.10.803
  83. Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983;301(5900):527-30. https://doi.org/10.1038/301527a0
  84. Grody WW, Fligiel S, Naeim F. Thymus involution in the acquired immunodeficiency syndrome. Am J Clin Pathol. 1985;84(1):85-95. https://doi.org/10.1093/ajcp/84.1.85
  85. Savino W. The thymus is a common target organ in infectious diseases. PLoS Pathog. 2006;2(6):e62. https://doi.org/10.1371/journal.ppat.0020062
  86. Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer. 2003;3(9):666-75. https://doi.org/10.1038/nrc1167
  87. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299-308. https://doi.org/10.1038/nrc2355
  88. Zhang W. CAR T-cell therapy: opportunities and challenges. Immunotherapy. 2016;8(3):245-7. https://doi.org/10.2217/imt.15.129

Cited by

  1. Bioengineering of Artificial Antigen Presenting Cells and Lymphoid Organs vol.7, pp.14, 2016, https://doi.org/10.7150/thno.19017
  2. Biomaterials innovation for next generation ex vivo immune tissue engineering vol.130, pp.None, 2017, https://doi.org/10.1016/j.biomaterials.2017.03.015
  3. TCR Sequencing Reveals the Distinct Development of Fetal and Adult Human Vγ9Vδ2 T Cells vol.203, pp.6, 2016, https://doi.org/10.4049/jimmunol.1900592
  4. Fibronectin-Functionalized Fibrous Meshes as a Substrate to Support Cultures of Thymic Epithelial Cells vol.21, pp.12, 2016, https://doi.org/10.1021/acs.biomac.0c00933
  5. Recent Advancements in Regenerative Approaches for Thymus Rejuvenation vol.8, pp.14, 2016, https://doi.org/10.1002/advs.202100543
  6. Recapitulation of Thymic Function by Tissue Engineering Strategies vol.10, pp.20, 2016, https://doi.org/10.1002/adhm.202100773