.2020 Dec 11;11(1):6372.

doi: 10.1038/s41467-020-20082-7.

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

Sara Campinoti^{1 2}, Asllan Gjinovci^{1 3}, Roberta Ragazzini^{1 3}, Luca Zanieri^{1 3}, Linda Ariza-McNaughton⁴, Marco Catucci^{1 2 5}, Stefan Boeing⁶, Jong-Eun Park^{7 8}, John C Hutchinson^{2 9}, Miguel Muñoz-Ruiz¹⁰, Pierluigi G Manti^{11 12}, Gianluca Vozza^{11 12}, Carlo E Villa¹¹, Demetra-Ellie Phylactopoulos^{1 2}, Constance Maurer^{1 2}, Giuseppe Testa^{11 12}, Hans J Stauss³, Sarah A Teichmann⁷, Neil J Sebire^{2 9}, Adrian C Hayday^{10 13}, Dominique Bonnet⁴, Paola Bonfanti^{14 15 16}

Affiliations

¹ Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
² UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
³ Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, NW3 2PF, UK.
⁴ Haematopoietic Stem Cell laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁵ Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, DIBIT 20132, Milan, Italy.
⁶ Bioinformatics Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁷ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
⁸ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
⁹ Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 1EH, UK.
¹⁰ Immunosurveillance laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
¹¹ Department of Experimental Oncology, IEO, European Institute of Oncology, IRCCS, Milan, Italy.
¹² Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
¹³ Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK.
¹⁴ Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. p.bonfanti@ucl.ac.uk.
¹⁵ UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. p.bonfanti@ucl.ac.uk.
¹⁶ Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, NW3 2PF, UK. p.bonfanti@ucl.ac.uk.

PMID:33311516
PMCID: PMC7732825
DOI: 10.1038/s41467-020-20082-7

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

Sara Campinoti et al. Nat Commun.2020.

.2020 Dec 11;11(1):6372.

doi: 10.1038/s41467-020-20082-7.

Authors

Affiliations

¹ Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
² UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
³ Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, NW3 2PF, UK.
⁴ Haematopoietic Stem Cell laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁵ Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, DIBIT 20132, Milan, Italy.
⁶ Bioinformatics Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁷ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
⁸ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
⁹ Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 1EH, UK.
¹⁰ Immunosurveillance laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
¹¹ Department of Experimental Oncology, IEO, European Institute of Oncology, IRCCS, Milan, Italy.
¹² Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
¹³ Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK.
¹⁴ Epithelial Stem Cell Biology & Regenerative Medicine laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. p.bonfanti@ucl.ac.uk.
¹⁵ UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. p.bonfanti@ucl.ac.uk.
¹⁶ Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Royal Free Hospital, London, NW3 2PF, UK. p.bonfanti@ucl.ac.uk.

PMID:33311516
PMCID: PMC7732825
DOI: 10.1038/s41467-020-20082-7

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.

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Conflict of interest statement

P.B. and A.G. are named inventors of patent application no. PCT/GB2019/051310. The remaining authors declare no competing interests.

Figures

**Fig. 1. Prospective isolation of thymic epithelial (TEC) and interstitial cells (TIC).**
a Left panel: Rhodamine-B staining of TEC: 500 cultured TEC were seeded in a dish for colony-forming efficiency (CFE); the dish was stained after 12 days of culture. TEC gave rise to colonies of variable sizes that stained differently with Rhodamine. Scale bar, 2 cm. Right panel: growth curve over serial weekly passaging of TEC (X axis, number of weekly passages;Y axis, cumulative cell number); significance, mean ± SD (n = 3; donor age from 2 months to 4 years).b Left panel: immunofluorescence labelling of thymic epithelial cells in human post-natal thymus where anti-CD205 antibody (green) marked cortical TEC (cTEC) and anti-CK5-14 (red) marked medullary TEC (mTEC). Scale bar, 50 μm. Right panel: FACS plot visualising cTEC (EpCAM^lowCD205⁺, 4.87%), mTEC (EpCAM^highCD205⁻, 11.1%) and TIC (EpCAM⁻CD205⁻, 61.5%) in the CD45-negative population enriched for sorting (n = 18; age from 3 days to 6 years). Representative analysis, thymus donor age 4 months (live cells = 51600).c FACS plots showing CD90 expression in enriched EpCAM^high mTEC (red), EpCAM^low cTEC (green) and EpCAM⁻ TIC (blue) respectively. Gating was decided on negative unstained control value for each channel. Same thymus as in 1b.d Representative FACS analysis for CD49f and CD90 demonstrating CD49f⁺ (Type1) and CD49f⁻ (Type2) populations. Same thymus as in 1b and 1c.e Rhodamine-stained indicator dishes of sorted cTEC and mTEC subtypes (4000 events/dish) cultivated for 12 days, colony-forming efficiency (CFE). mTEC^Type1 is the most clonogenic population (2–4%) and cTEC^Type1 (1–2%) is the clonogenic population of the cortex (n = 4).f Growth curve over serial weekly passaging of sorted mTEC^Type1 and cTEC^Type1 (X axis, number of weekly passages;Y axis, cumulative cell number;n = 4 independent cultures; data are presented as mean value ± SE; donor age from 2 months to 4 years old).g Gene expression signature of cultivated clonogenic TEC (unsorted, black), medullary (Type1 mTEC, red) and cortical TEC (Type1 cTEC, green). Heatmap and hierarchical clustering of samples according to expression of thymic identity genes (*SIX1, EYA1, PAX1* andPAX9), markers of thymic cortex (*CTSV, PRSS16* andLY75) and medulla (*CD24* andCDH1).

**Fig. 2. Single-cell RNA sequencing of freshly isolated TEC defines common cell clusters to mTEC and cTEC that are maintained in vitro.**
a UMAP visualisation of the cellular composition of the human post-natal thymus by clusters indicated by colours and numbers from 1 to 15 describing the heterogeneity of cTEC (1–3) and mTEC (7-11). Clusters 12–15 were common to cortex and medulla (comTEC); clusters 4–6 described residual immune cells (PMNs, DCs and thymocytes).b UMAP representation of the same thymic cells indicating main subgroups (cTEC, cortical epithelial cells, in green; mTEC, medullary epithelial cells, in red; TEC cells with common features, in brown and residuals of immune cells in grey).c Area under the curve (AUC) summary intensity plots for the gene signatures of cTEC (*CCL25, CD274, CFC1, CTSV, FOXN1, KCNIP3, LY75, PRSS16, PSMB11, SCX, SLC46A2, TBATA* andTP53AIP1), mTEC (*CD24, CDH1, CLDN3, EPCAM* andHES6) and comTEC (*CCL19, CFTR, COL1A1, DAB2, FN1, GLIPR2, HAS2, HGF, KRT14, KRT15, LOXL2, MKI67, MMP2, S100A4, SNAI1, SNAI2, TFCP2L1, TGFB3, TGFBR2, THY1, TP63, TWIST1* andZEB1) clusters showing expression level for lineage specific genes in a purple scale. Single-cell expression values are represented as calculated median intensity of area under the curve.d Heatmap and hierarchical clustering of cultured cTEC^Type1 (green,n = 3), mTEC^Type1 (red,n = 3) and cultured unsorted TEC (black,n = 2) according to main genes clusters defined in single-cell RNA sequencing. Genes list is displayed on the right and includes comTEC signatures (epithelial-to-mesenchymal transition (EMT), polykeratins and proliferative - clusters 12-13-14) and specialised cell clusters: Myo (clusters 7-8), Neuro (clusters 9–10), Ionocytes (cluster 15) and differentiated mTEC (cluster 11).

**Fig. 3. Phenotypic analysis of in vitro expanding thymic stromal cells.**
a Immunofluorescence labelling of thymic epithelial cells in human post-natal thymus where CK8-18 antibody (yellow), CK5-14 or CD49f (magenta) marked TEC. Tissues contains healthy cells as shown by absence of CASP3 (top mid panel). Co-staining with CD90 (top left panel), vimentin (VIM, top mid panel) or TE7 (top right panel) in green shows epithelial cells with mesenchymal features. Bottom panel shows co-expression of VIM (green), CK8-18 (yellow) and transcription factor TP63 (magenta). Arrow and inserts (white) highlight individual cells with hybrid phenotype. Nuclei are stained with DAPI. Scale bar, 50 μm (n = 4 thymi).b Immunofluorescence labelling of epithelial and mesenchymal markers on expanding thymic epithelial cells colonies expressing CD90 (left panels), VIM (middle panels) and TE7 (right panels) in green. Most of TEC in culture co-express cytokeratin CK5-14 (magenta) and CK8-18 (yellow), CD49f (magenta) together with mesenchymal markers. Bottom panels: left, TEC express proliferation marker MKI67 (green) and right panels: TEC co-express transcription factor TP63 (magenta) with VIM (green). Nuclei are stained with DAPI (n = 4 independent cultures). Scale bar, 50 μm.c Left panel: phase contrast image of thymic interstitial cells (TIC) expanded after sorting. Scale bar, 200 μm. Right panel: growth curve shows TIC expansion over several weekly passages (n = 4 independent cultures, data are presented as mean value ± S.D.).d Immunofluorescence of cultivated TIC demonstrates protein expression for TE7 and vimentin (VIM), as well as PDGFRβ, NG2 and Smooth Muscle Actin (αSMA),n = 3 independent cultures. Scale bar, 40 μm.e, Representative FACS analysis of expanded TIC for mesoderm markers PDGFRα (PE), PDGFRβ (PE),n = 5 independent cultures.

**Fig. 4. Whole-organ thymus perfusion and decellularisation.**
a Gross appearance of cannulated rat thymi before (upper panels) and after (lower panels) decellularisation. A 24G cannula is inserted into the carotid artery and used to perfuse the organ with detergent and enzymatic solutions. Asterisks indicate extra-thymic tissues that allowed connection between thymic tissue and cannula through the large blood vessels (n = 120). Scale bar, 2 mm.b Micro-CT images of cannulated rat thymus showing extra-thymic tissues, large blood vessels and the 24G cannula entering the artery. Iodine contrast shows clear demarcation between cortex (C, bright) and medullary (M) areas; blood vessels (asterisks) are represented by very bright areas between and inside the parenchyma (n = 3). Scale bar, 1.5 mm.c Micro-CT 3D image of whole rat thymus cannulated where iodine contrast shows vasculature tree (segmented in red,n = 2). Scale bar, 1.2 mm.d Masson’s trichrome stain of a fresh rat thymus lobe staining in red keratins, in blue collagen and in pink cytoplasm. C cortex, M medulla (n = 3 thymi). Scale bar, 250 μm.e Haematoxylin & Eosin (H&E) stain of a fresh rat thymus. C cortex, M medulla (n = 3 thymi). Scale bar, 500 μm.f Micro-CT image of cannulated rat thymus showing the whole 2 lobes in 3D. Scale bar, 1.2 mm.g Micro-CT image of a cannulated rat thymus injected with Microfil® and thresholded to demonstrate perfusion of both thymic lobes. Scale bar, 1.2 mm.h Masson’s trichrome stain of a paraffin section of a decellularised rat thymus scaffold demonstrating collagen fibres (blue) and absence of keratins, muscle fibres and cell cytoplasm (n = 3 scaffolds). Scale bar, 250 μm.i H&E of a decellularised thymus scaffold showing intact thymic lobule ECM and preservation of both large and small vasculature wall (n = 4 scaffolds). Scale bar, 500 μm.

**Fig. 5. Functional repopulation of whole-organ thymus scaffolds.**
a Gross microscopy representative of a thymus scaffold before (left panel), soon after injection of stromal cells (middle panel) and following 4 days of culture (right panel). Thymic lobes from empty progressively increase density and get remodelled as shown by shrinking of the scaffold and increase tissue volume (n = 60 repopulated scaffolds). Scale bar, 4 mm.b Immunofluorescence labelling of thymic epithelial cells (TEC) grown within a decellularised scaffold demonstrating presence of CK5-14⁺, TP63⁺ and CD49f⁺ TEC. Nuclei are stained with DAPI (n = 4 repopulated scaffolds). Scale bar, 30 μm.c H&E staining shows histology of a scaffold repopulated only with TEC and cultivated for 5 days (n = 4 repopulated scaffolds). Scale bar, 50 μm.d Haematoxyin & Eosin (H&E) staining of a scaffold repopulated with both expanded clonogenic TEC and thymic interstitial cells (TIC) and cultivated for 5 days prior to fixation and histological analysis. Stromal cells reorganise along the scaffold with a pattern similar to the one (e) observed in early (9-week post-conception, wpc) human foetal thymus (n = 4 repopulated scaffolds andn = 2 human foetal thymi). Scale bar, 100 μm.f Immunofluorescence labelling of TEC seeded together with TIC and grown within a decellularised scaffold demonstrating CK5-14⁺ cells localised in the subcapsular region while CK8⁺ cells prevalently localised in the inner regions; TP63⁺ TEC were mainly CD49f⁺. Nuclei are stained with DAPI (n = 4 repopulated scaffolds). Scale bar, 100 μm.g H&E staining of a scaffold repopulated with TEC, TIC and haematopoietic progenitors after 7 days of culture (n = 4 repopulated scaffolds). Scale bar, 100 μm.h Representative FACS analysis (n = 6 repopulated scaffold in three independent experiments) of CD45-positive population isolated from repopulated scaffold seeded with triple negative (TN, CD3⁻CD4⁻CD8⁻) progenitors and co-cultured for 8 days. The FSC-A, SSC-A plot displays the presence of cells as well as of debris derived from the scaffold ECM during dissociation for release of haematopoietic cells (top left panel). Viable cells were ~90% of total cells (top mid panel). TN developed within the scaffold gave rise to double positive (DP) and single positive (SP) CD4 and CD8 expressing cells (top right panel, 5000 cells). Live cells were positive for CD1a and negative for CD33 (bottom right panel). CD4 and CD8 were positive for CD3 and express TCRαβ (bottom mid and left panel).

**Fig. 6. Repopulated thymus scaffolds mature in vivo and promote functional T cell development.**
a H&E staining of histological sections of thymic scaffolds harvested at different time points post-transplant (8, 11, 18 and 22 wpt). Asterisks indicates Hassall’s Bodies (HB); n = 18 scaffolds in 3 independent experiments. Scale bar, 100 μm.b H&E of histological section of a thymic scaffold not seeded with CD34⁺ HSC at grafting and harvested at 18 wpt; Asterisks indicates Hassall’s Bodies (HB). Scale bar, 100 μm.c Immunofluorescence analysis for CD3, E-Cadherin, CK5, Vimentin (VIM) and mouse Endomucin (Emcn) at 11 wpt for thymic scaffolds repopulated with stroma and CD34⁺ HSC;n = 4 scaffolds in two independent experiments. Scale bar, 50 μm.d Immunohistochemistry for AIRE-1 of thymus scaffolds harvested at 11, 18 and 22 wpt demonstrate progressive increase of AIRE-1⁺ cells;n = 8 scaffolds in three independent experiments. Scale bar, 50 μm.e HLA-DR was detected in cytokeratin-positive medullary (CK5) and cortical (CK8) cells in repopulated scaffolds by immunofluorescence;n = 18 scaffolds in three independent experiments. Scale bar, 25 μm.f Representative FACS analysis of a dissociated thymic scaffold at 11 wpt showing presence of CD3⁺ cells (80% of total human (h) CD45⁺ population;n = 9 scaffolds).g FACS analysis of dissociated thymic scaffolds demonstrates both double positive (DP) and single positive (SP) CD4 and CD8 cells. SP CD4 and CD8 cells also expressed CD3 and TCRαβ, demonstrating the presence of immature single positive (ISP) as well as fully mature thymocytes at both 11 wpt and 18 wpt time points (n = 9 scaffolds, live cells = 1100–3800).h Representative FACS analysis of sorted and in vitro expanded CD3⁺ cells. CD3⁺ cells were sorted either from repopulated thymus scaffolds or from the endogenous NSG thymus 18 wpt, expanded in vitro prior to FACS analysis that shows presence of CD4⁺ and CD8⁺ SP cells. Expanded CD4⁺ and CD8⁺ cells were stimulated by PMA-ionomycin and intracellular cytokine staining performed: CD4⁺ and CD8⁺ isolated from endogenous mouse thymus were able to produce IL2, TNFα and IFNγ, while SP CD4 and CD8 cells developed within thymus scaffolds were able to produce only limited amount of IL2. CD8 SP cells, though in minor number in each scaffold compared to CD4⁺ were able to produce the highest level of IFNγ and TNFα;n = 2 independent experiments (live cells from scaffolds = 7000 and from endogenous thymus = 52000).

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

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

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