Single-Cell RNA Sequencing Resolves Spatiotemporal Development of Pre-thymic Lymphoid Progenitors and Thymus Organogenesis in Human Embryos

Zeng, Yang; Liu, Chen; Gong, Yandong; Bai, Zhijie; Hou, Siyuan; He, Jian; Bian, Zhilei; Li, Zongcheng; Ni, Yanli; Jing, Yan; Huang, Tao; Shi, Hui; Ma, Chunyu; Chen, Xueying; Wang, Jinyong; Bian, Lihong; Lan, Yu; Liu, Bing; Hu, Hongbo

doi:10.1016/j.immuni.2019.09.008

Cited by 104 publications

(153 citation statements)

References 120 publications

(149 reference statements)

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“…Nevertheless, our work nuances previous findings by suggesting that at least two distinct populations can seed the thymus, thereby also reconciling these studies. Importantly, these TSP subpopulations differ from the recently described human fetal TSPs (Zeng et al, 2019) which where shown to express high levels of IL3RA , IRF8 and IL6R . The unique transcriptional profile of the postnatal TSPs will clearly be important from a translational perspective to improve T cell reconstitution in patients following for instance hematopoietic stem cell transplantations.…”

Section: Discussioncontrasting

confidence: 64%

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors

Lavaert

Vandamme

et al. 2020

Preprint

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During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone marrow derived hematopoietic progenitors that migrate through the bloodstream. In human, the nature of these thymus immigrants has remained unclear. Here, we employ single-cell RNA sequencing on approximately 70.000 CD34 + thymocytes to unravel the heterogeneity of the human immature postnatal thymocytes. Integration of bone marrow and peripheral blood precursors datasets identifies several putative thymus seeding precursors that display heterogeneity for currently used surface markers as revealed by CITEseq. Besides T cell precursors, we discover branches of intrathymic developing dendritic cells with predominantly plasmacytoid DCs. Trough trajectory inference, we delineate the transcriptional dynamics underlying early human T-lineage development from which we predict transcription factor modules that drive stage-specific steps of human T cell development. Thus, our work resolves the heterogeneity of thymus seeding precursors in human and reveals the molecular mechanisms that drive their in vivo cell fate.

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Section: Discussioncontrasting

confidence: 64%

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors

Lavaert

Vandamme

et al. 2020

Preprint

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“…In this issue of Immunity, Zeng et al present the first glimpses of how individual cells in the early human fetus develop into a thymus and begin to produce T cells (Zeng et al, 2019). The thymus is the ''factory'' in which small numbers of immigrating blood-cell precursors are driven through extensive proliferation and differentiation to generate T cells of diverse types.…”

Section: Building a Human Thymus: A Pointillist Viewmentioning

confidence: 99%

“…Genes associated with later (post-commitment) stages of mouse T cell development, including Bcl11b, the Cd3 genes, Cd4, Cd8a, and Cd8b, already seem to be expressed by earlyfetal human precursors in clusters that are still predicted to have an otherwise primitive cell-surface marker phenotype (CD34+ CD7+ CD1aÀ). Cluster definition in single-cell analysis is always provisional, and gene expression levels averaged across a clustered population, as in the results shown (Zeng et al, 2019), might not apply to every cell in the cluster. Still, the data suggest that in this initial human T cell developmental wave there may be an accelerated activation of later T-lineage genes before the cells lose their early-precursor phenotype.…”

Section: Immunitymentioning

confidence: 99%

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Building a Human Thymus: A Pointillist View

Zhou

Rothenberg

2019

Immunity

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“…Accumulated developmental evidence shows that blood progenitors prior to the occurrence of definitive HSC, also possess T cell lineage differentiation potential 14–17 . Despite the abundant knowledge of the pivotal transcription factors regulating T cell development from HSC derivatives 18 , intrinsic determinants of T cell lineage potential in the HSC-independent hematopoietic progenitors at the pre-liver and pre-thymus stages remain elusive.…”

Section: Introducationmentioning

confidence: 99%

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

Guo

Weng

et al. 2019

Preprint

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30 Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent 31 stem cells is a central aim in T cell regenerative medicine. To date, preferentially 32 regenerating T lymphopoiesis in vivo from pluripotent stem cells (PSC) remains a 33 practical challenge. Here we documented that synergistic and transient expression of 34 Runx1 and Hoxa9 restricted in the time window of endothelial to hematopoietic 35 transition and hematopoietic maturation stages induced in vitro from PSC (iR9-PSC) 36 preferentially generated engraftable hematopoietic progenitors capable of homing to 37 thymus and developing into mature T (iT) cells in primary and secondary 38 immunodeficient recipients. Single-cell transcriptome and functional analyses 39 illustrated the cellular trajectory of T lineage induction from PSC, unveiling the 40 T-lineage specification determined at as early as hemogenic endothelial cell stage and 41 identifying the bona fide pre-thymic progenitors. The iT cells distributed normally in 42 central and peripheral lymphoid organs and exhibited abundant TCRαβ repertoire. 43 The regenerative T lymphopoiesis rescued the immune-surveillance ability in 44 3 immunodeficient mice. Furthermore, gene-edited iR9-PSC produced tumor-specific-T 45 cells in vivo that effectively eradicated tumor cells. This study provides insight into 46 universal generation of functional and therapeutic T lymphopoiesis from the unlimited 47 and editable PSC source. 48 lymphopoiesis 50 INTRODUCATION 51A prominent method to generate T cells is an in vitro system via co-culture of either 52 mouse or human hematopoietic stem/progenitors (HSPC) with stromal cell lines 53 expressing the Notch ligand, such as OP9-DL1/DL4 or 3D-based MS5-hDLL1/4 1-3 . 54Despite the great contribution of this approach to studying T cell development in vitro, 55 phenotypic T cells produced by this approach face severe immunocompetency 56 problems in vivo after engraftment, due to the inadequate in vitro recapitulation of 57 natural thymus microenvironment. Natural mouse Sca1 + cKit + and human CD34 + 58 blood progenitor cells can be induced into CD7 + pre-thymic cells in vitro, which 59 successfully colonize thymi and mature into immunocompetent T cells in vivo 4,5 . 60However, this in vitro plus in vivo two-step approach never succeeded in generating 61 induced T lymphopoiesis when starting from pluripotent stem cells (PSC), as induced 62 T cell progenitors from PSC showed intrinsic thymus-homing defect in vivo 6 . 63 Another prevailing concept for generating functional T lymphopoiesis from PSC is 64 via induction of hematopoietic stem cell (HSC)-like intermediates followed by in vivo 65 multi-lineage hematopoiesis, including T cells 7-10 . However, generating robust bona 66 4 fide induced-HSC (iHSC) from PSC remains inefficient 11,12 and whether this 67 approach can generate therapeutic tumor-killing T cells is unknown. Recently, Hoxb5 68 is shown to convert natural B cells into functional T cells in vivo 13 , providing an 69 alternative method to shor...

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Single-Cell RNA Sequencing Resolves Spatiotemporal Development of Pre-thymic Lymphoid Progenitors and Thymus Organogenesis in Human Embryos

Cited by 104 publications

References 120 publications

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors

Building a Human Thymus: A Pointillist View

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

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