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, J. Ciaran Hutchinson, Miguel Muñoz‐Ruiz, Pierluigi Giuseppe Manti, Gianluca Vozza, Carlo Emanuele Villa, D Phylactopoulos, Constance Maurer, Giuseppe Testa, Hans J. Stauss, Sarah A. Teichmann, Neil J. Sebire, Adrian Hayday, Dominique Bonnet, Paola Bonfanti
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.