De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids.
Journal
Nature methods
ISSN: 1548-7105
Titre abrégé: Nat Methods
Pays: United States
ID NLM: 101215604
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
22
09
2020
accepted:
18
07
2022
pubmed:
7
9
2022
medline:
13
10
2022
entrez:
6
9
2022
Statut:
ppublish
Résumé
Hematopoietic humanized (hu) mice are powerful tools for modeling the action of human immune system and are widely used for preclinical studies and drug discovery. However, generating a functional human T cell compartment in hu mice remains challenging, primarily due to the species-related differences between human and mouse thymus. While engrafting human fetal thymic tissues can support robust T cell development in hu mice, tissue scarcity and ethical concerns limit their wide use. Here, we describe the tissue engineering of human thymus organoids from inducible pluripotent stem cells (iPSC-thymus) that can support the de novo generation of a diverse population of functional human T cells. T cells of iPSC-thymus-engrafted hu mice could mediate both cellular and humoral immune responses, including mounting robust proinflammatory responses on T cell receptor engagement, inhibiting allogeneic tumor graft growth and facilitating efficient Ig class switching. Our findings indicate that hu mice engrafted with iPSC-thymus can serve as a new animal model to study human T cell-mediated immunity and accelerate the translation of findings from animal studies into the clinic.
Identifiants
pubmed: 36064772
doi: 10.1038/s41592-022-01583-3
pii: 10.1038/s41592-022-01583-3
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1306-1319Subventions
Organisme : NIAID NIH HHS
ID : R01 AI123392
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI126335
Pays : United States
Organisme : NIH HHS
ID : S10 OD019973
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).
pubmed: 14978070
doi: 10.4049/jimmunol.172.5.2731
Shultz, L. D. et al. Humanized mouse models of immunological diseases and precision medicine. Mamm. Genome 30, 123–142 (2019).
pubmed: 30847553
pmcid: 6610695
doi: 10.1007/s00335-019-09796-2
Walsh, N. C. et al. Humanized mouse models of clinical disease. Annu Rev. Pathol. 12, 187–215 (2017).
pubmed: 27959627
doi: 10.1146/annurev-pathol-052016-100332
Ito, R., Takahashi, T., Katano, I. & Ito, M. Current advances in humanized mouse models. Cell Mol. Immunol. 9, 208–214 (2012).
pubmed: 22327211
pmcid: 4012844
doi: 10.1038/cmi.2012.2
Melkus, M. W. et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat. Med. 12, 1316–1322 (2006).
pubmed: 17057712
doi: 10.1038/nm1431
Lan, P., Tonomura, N., Shimizu, A., Wang, S. & Yang, Y. G. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34
pubmed: 16410443
doi: 10.1182/blood-2005-11-4388
Shultz, L. D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).
pubmed: 15879151
doi: 10.4049/jimmunol.174.10.6477
Boehm, T. & Bleul, C. C. Thymus-homing precursors and the thymic microenvironment. Trends Immunol. 27, 477–484 (2006).
pubmed: 16920024
doi: 10.1016/j.it.2006.08.004
Hedrick, S. M. Thymus lineage commitment: a single switch. Immunity 28, 297–299 (2008).
pubmed: 18342002
doi: 10.1016/j.immuni.2008.02.011
Klein, L., Hinterberger, M., Wirnsberger, G. & Kyewski, B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat. Rev. Immunol. 9, 833–844 (2009).
pubmed: 19935803
doi: 10.1038/nri2669
Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).
pubmed: 24830344
pmcid: 4757912
doi: 10.1038/nri3667
Anderson, G. & Takahama, Y. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 33, 256–263 (2012).
pubmed: 22591984
doi: 10.1016/j.it.2012.03.005
Ohigashi, I., Kozai, M. & Takahama, Y. Development and developmental potential of cortical thymic epithelial cells. Immunol. Rev. 271, 10–22 (2016).
pubmed: 27088904
doi: 10.1111/imr.12404
Klug, D. B. et al. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl Acad. Sci. USA 95, 11822–11827 (1998).
pubmed: 9751749
pmcid: 21724
doi: 10.1073/pnas.95.20.11822
Mizuochi, T., Kasai, M., Kokuho, T., Kakiuchi, T. & Hirokawa, K. Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells. J. Exp. Med. 175, 1601–1605 (1992).
pubmed: 1534114
doi: 10.1084/jem.175.6.1601
Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2, 1032–1039 (2001).
pubmed: 11600886
doi: 10.1038/ni723
Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat. Immunol. 11, 512–519 (2010).
pubmed: 20431619
doi: 10.1038/ni.1874
Tajima, A., Pradhan, I., Geng, X., Trucco, M. & Fan, Y. Construction of thymus organoids from decellularized thymus scaffolds. Methods Mol. Biol. 1576, 33–42 (2019).
pubmed: 27730537
pmcid: 5389928
doi: 10.1007/7651_2016_9
Hun, M. et al. Native thymic extracellular matrix improves in vivo thymic organoid T cell output, and drives in vitro thymic epithelial cell differentiation. Biomaterials 118, 1–15 (2017).
pubmed: 27940379
doi: 10.1016/j.biomaterials.2016.11.054
Fan, Y. et al. Bioengineering thymus organoids to restore thymic function and induce donor-specific immune tolerance to allografts. Mol. Ther. 23, 1262–1277 (2015).
pubmed: 25903472
pmcid: 4817796
doi: 10.1038/mt.2015.77
Campinoti, S. et al. Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds. Nat. Commun. 11, 6372 (2020).
pubmed: 33311516
pmcid: 7732825
doi: 10.1038/s41467-020-20082-7
Shi, Y., Inoue, H., Wu, J. C. & Yamanaka, S. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug Disco. 16, 115–130 (2017).
doi: 10.1038/nrd.2016.245
Parent, A. V. et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13, 219–229 (2013).
pubmed: 23684540
doi: 10.1016/j.stem.2013.04.004
Sun, X. 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, 230–236 (2013).
pubmed: 23910085
doi: 10.1016/j.stem.2013.06.014
Okabe, M., Ito, S., Nishio, N., Tanaka, Y. & Isobe, K. Thymic epithelial cells induced from pluripotent stem cells by a three-dimensional spheroid culture system regenerates functional T cells in nude mice. Cell Reprogram. 17, 368–375 (2015).
pubmed: 26348437
doi: 10.1089/cell.2015.0006
Chhatta, A. R. et al. De novo generation of a functional human thymus from induced pluripotent stem cells. J. Allergy Clin. Immunol. 144, 1416–1419 e1417 (2019).
pubmed: 31323248
doi: 10.1016/j.jaci.2019.05.042
Ramos, S. A. et al. Generation of functional human thymic cells from induced pluripotent stem cells. J. Allergy Clin. Immunol. https://doi.org/10.1016/j.jaci.2021.07.021 (2021)
Richardson, T., Kumta, P. N. & Banerjee, I. Alginate encapsulation of human embryonic stem cells to enhance directed differentiation to pancreatic islet-like cells. Tissue Eng. Part A 20, 3198–3211 (2014).
pubmed: 24881778
pmcid: 4259202
doi: 10.1089/ten.tea.2013.0659
Bredenkamp, N. et al. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat. Cell Biol. 16, 902–908 (2014).
pubmed: 25150981
pmcid: 4153409
doi: 10.1038/ncb3023
Rodewald, H.-R. Thymus organogenesis. Annu. Rev. Immunol. 26, 355–388 (2008).
pubmed: 18304000
doi: 10.1146/annurev.immunol.26.021607.090408
Bonfanti, P. et al. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466, 978–982 (2010).
pubmed: 20725041
doi: 10.1038/nature09269
Park, J.-E. et al. A cell atlas of human thymic development defines T cell repertoire formation. Science https://doi.org/10.1126/science.aay3224 (2020)
Takahama, Y., Ohigashi, I., Baik, S. & Anderson, G. Generation of diversity in thymic epithelial cells. Nat. Rev. Immunol. 17, 295–305 (2017).
pubmed: 28317923
doi: 10.1038/nri.2017.12
Irla, M. in Thymus Transcriptome and Cell Biology (ed. Passos, G. A.) 149–167 (Springer International Publishing, 2019).
Rothenberg, E. V. Single-cell insights into the hematopoietic generation of T-lymphocyte precursors in mouse and human. Exp. Hematol. https://doi.org/10.1016/j.exphem.2020.12.005 (2021).
doi: 10.1016/j.exphem.2020.12.005
pubmed: 33454362
pmcid: 8018899
Czechowicz, A., Kraft, D., Weissman, I. L. & Bhattacharya, D. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 318, 1296–1299 (2007).
pubmed: 18033883
pmcid: 2527021
doi: 10.1126/science.1149726
Brehm, M., Daniels, K. & Welsh, R. Rapid production of TNF-alpha following TCR engagement of naive CD8 T cells. J. Immunol. 175, 5043–5049 (2005).
Kooreman, N. G. et al. Alloimmune responses of humanized mice to human pluripotent stem cell therapeutics. Cell Rep. 20, 1978–1990 (2017).
pubmed: 28834758
pmcid: 5573767
doi: 10.1016/j.celrep.2017.08.003
Jangalwe, S., Shultz, L. D., Mathew, A. & Brehm, M. A. Improved B cell development in humanized NOD-scid IL2Rγnull mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3. Immun. Inflamm. Dis. 4, 427–440 (2016).
pubmed: 27980777
pmcid: 5134721
doi: 10.1002/iid3.124
Billerbeck, E. et al. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγnull humanized mice. Blood 117, 3076–3086 (2011).
pubmed: 21252091
pmcid: 3062310
doi: 10.1182/blood-2010-08-301507
Yu, H. et al. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood 129, 959–969 (2017).
pubmed: 28077418
pmcid: 5324713
doi: 10.1182/blood-2016-04-709584
Brehm, M. A. et al. Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin. Immunol. 135, 84–98 (2010).
pubmed: 20096637
pmcid: 2835837
doi: 10.1016/j.clim.2009.12.008
Fares, I. et al. EPCR expression marks UM171-expanded CD34+ cord blood stem cells. Blood 129, 3344–3351 (2017).
pubmed: 28408459
doi: 10.1182/blood-2016-11-750729
Khosravi-Maharlooei, M. et al. Cross-reactive public TCR sequences undergo positive selection in the human thymic repertoire. J. Clin. Invest. 129, 2446–2462 (2019).
Rossi, S. W. et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109, 3803–3811 (2007).
pubmed: 17213286
pmcid: 1874572
doi: 10.1182/blood-2006-10-049767
Mantri, S. et al. CD34 expression does not correlate with immunophenotypic stem cell or progenitor content in human cord blood products. Blood Adv. 4, 5357–5361 (2020).
pubmed: 33136125
pmcid: 7656928
doi: 10.1182/bloodadvances.2020002891
Fares, I. et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509–1512 (2014).
pubmed: 25237102
pmcid: 4372335
doi: 10.1126/science.1256337
Cohen, S. et al. Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1–2 safety and feasibility study. Lancet Haematol. 7, e134–e145 (2020).
pubmed: 31704264
doi: 10.1016/S2352-3026(19)30202-9
Tomellini, E. et al. Integrin-α3 Is a functional marker of ex vivo expanded human long-term hematopoietic stem cells. Cell Rep. 28, 1063–1073.e1065 (2019).
pubmed: 31340144
doi: 10.1016/j.celrep.2019.06.084
Tan, Y.-T. et al. Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor. Proc. Natl Acad. Sci. USA 115, 2180–2185 (2018).
pubmed: 29386396
pmcid: 5834708
doi: 10.1073/pnas.1718446115
Hoggatt, J. et al. Rapid mobilization reveals a highly engraftable hematopoietic stem cell. Cell 172, 191–204.e110 (2018).
pubmed: 29224778
doi: 10.1016/j.cell.2017.11.003
Sugimura, R. et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438 (2017).
pubmed: 28514439
pmcid: 5872146
doi: 10.1038/nature22370
Richardson, T. et al. in Programmed Morphogenesis: Methods and Protocols Methods in Molecular Biology (eds Ebrahimkhani, M. R. & Hislo, J.) 73–92 (Springer, 2021).
Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. J. Stat. Mech. 2008, P10008 (2008).
doi: 10.1088/1742-5468/2008/10/P10008