Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds

Sara Campinoti, Asllan Gjinovci, Roberta Ragazzini, Luca Zanieri, Linda Ariza-McNaughton, Marco Catucci, Stefan Boeing, Jong-Eun Park, John C. Hutchinson, Miguel Muñoz-Ruiz, Pierluigi G. Manti, Gianluca Vozza, Carlo E. Villa, Demetra-Ellie Phylactopoulos, Constance Maurer, Giuseppe Testa, Hans J. Stauss, Sarah A. Teichmann, Neil J. Sebire, Adrian C. Hayday, Dominique Bonnet and Paola Bonfanti ()
Additional contact information
Sara Campinoti: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Asllan Gjinovci: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Roberta Ragazzini: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Luca Zanieri: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Linda Ariza-McNaughton: Haematopoietic Stem Cell laboratory, The Francis Crick Institute
Marco Catucci: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Stefan Boeing: Bioinformatics Laboratory, The Francis Crick Institute
Jong-Eun Park: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton
John C. Hutchinson: UCL Great Ormond Street Institute of Child Health
Miguel Muñoz-Ruiz: Immunosurveillance laboratory, The Francis Crick Institute
Pierluigi G. Manti: IEO, European Institute of Oncology, IRCCS
Gianluca Vozza: IEO, European Institute of Oncology, IRCCS
Carlo E. Villa: IEO, European Institute of Oncology, IRCCS
Demetra-Ellie Phylactopoulos: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Constance Maurer: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute
Giuseppe Testa: IEO, European Institute of Oncology, IRCCS
Hans J. Stauss: Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital
Sarah A. Teichmann: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton
Neil J. Sebire: UCL Great Ormond Street Institute of Child Health
Adrian C. Hayday: Immunosurveillance laboratory, The Francis Crick Institute
Dominique Bonnet: Haematopoietic Stem Cell laboratory, The Francis Crick Institute
Paola Bonfanti: Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20082-7

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