TY - JOUR
T1 - Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds
AU - Campinoti, Sara
AU - Gjinovci, Asllan
AU - Ragazzini, Roberta
AU - Zanieri, Luca
AU - Ariza-McNaughton, Linda
AU - Catucci, Marco
AU - Boeing, Stefan
AU - Park, Jong Eun
AU - Hutchinson, John C.
AU - Muñoz-Ruiz, Miguel
AU - Manti, Pierluigi G.
AU - Vozza, Gianluca
AU - Villa, Carlo E.
AU - Phylactopoulos, Demetra Ellie
AU - Maurer, Constance
AU - Testa, Giuseppe
AU - Stauss, Hans J.
AU - Teichmann, Sarah A.
AU - Sebire, Neil J.
AU - Hayday, Adrian C.
AU - Bonnet, Dominique
AU - Bonfanti, Paola
N1 - Funding Information:
We would like to thank Ander Abarrategi, Giulio Cossu, Graham Davies, Paolo De Coppi, Deena Gibbons, Adam Laing, Daisy Melandri, Ben Seddon and Adrian Thrasher for helpful discussions. We are grateful to Evey Howley, Sahira Khalaf, Pei-Shi Chia and Nagarajan Muthialu for consenting patients for tissue donation; we thank the Advanced Sequencing team (particularly Amelia Edwards for her expert library preparation), the flow cytometry (Debipriya Das, Hefin Rhys, Andy Riddell), experimental histopathology (Emma Nye and team), electron microscopy (Marie-Charlotte Domart, Lucy Collinson), light microscopy (Rocco D’Antuono), the genomic park (Maria Greco, Graham Clark) and biological service units of the Francis Crick Institute; the flow cytometry team (Ayad Eddaoudi, Stephanie Cunning), the Biological Service Unit (Ailsa Greppi), the imaging facility (Dale Moulding) at the GOS Institute of Child Health and histopathology at the GOSH. We thank Erika Tenderini for library preparation (bulk RNA-seq). We thank the Joint MRC/Wellcome Trust Human Developmental Biology Resource (HDBR) for providing foetal tissue under informed ethical consent. A.G. dedicates this work to the late Professor Albert E. Renold. P.B. received funding from the European Research Council (ERC-Stg Agreement No. 639429), the Rosetrees Trust (M362; M362-F1; M553), the London Advanced Therapies - Research England (C2N-AT.006), the MRC Confidence in Concept scheme (Award: MC_PC_17180), and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust (NIHR GOSH BRC). D.B. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001045), The UK Medical Research Council (FC001045) and the Wellcome Trust (FC001045). A.C.H. is supported by funds from the Francis Crick Institute (FC001093) and by a WT Investigator Award (106292/Z/14/Z); M.M-R. is supported by the European Molecular Biology Organization (ALTF 198–2018); N.J.S. is part supported by GOSH Children’s Charity and NIHR GOSH BRC. P.G.M. is supported by a research fellowship (type A) of the University of Milan, Department of Oncology and Hemato-Oncology.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.
AB - The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.
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U2 - 10.1038/s41467-020-20082-7
DO - 10.1038/s41467-020-20082-7
M3 - Article
C2 - 33311516
AN - SCOPUS:85097510475
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 6372
ER -