Organoid-Induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells

Montel‐Hagen, Amélie; Seet, Christopher S.; Li, Suwen; Chick, Brent; Zhu, Yuhua; Chang, Peter; Tsai, Shau‐Wei; Sun, Victoria; Lopez, S. R.; Chen, Ho-Chung; He, Chongbin; Chin, Chee Jia; Casero, David

doi:10.1016/j.stem.2018.12.011

Cited by 170 publications

(178 citation statements)

References 52 publications

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“…OP9-DLL1, OP9-DLL4, and analogs based on the TSt4 cell line made it possible to dissect gene regulatory network circuitry and roles of signaling and transcription factors in T-cell commitment in real time, often at single-cell resolution. Whereas these monolayer systems were inefficient at mimicking the later stages of intrathymic T-cell development, a very recent cell linebased organoid culture system has proven to support more complete T-cell development, albeit at the cost of less proliferation than in OP9-based systems (Seet et al 2017;Montel-Hagen et al 2019). The mechanisms described in this review have been revealed and reinforced through combined use of in vivo and in vitro microenvironments for T-cell development.…”

Section: Background: the Thymic Microenvironmentsmentioning

confidence: 99%

Programming for T-lymphocyte fates: modularity and mechanisms

Rothenberg

2019

Genes Dev.

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T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.

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Section: Background: the Thymic Microenvironmentsmentioning

confidence: 99%

Programming for T-lymphocyte fates: modularity and mechanisms

Rothenberg

2019

Genes Dev.

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“…A prominent method to generate T cells is an in vitro system via co-culture of either mouse or human hematopoietic stem/ progenitors (HSPCs) with stromal cell lines expressing the Notch ligand, such as OP9-DL1/DL4 or 3D-based MS5-hDLL1/4. [1][2][3] Despite the great contribution of this approach to studying T cell development in vitro, phenotypic T cells produced by this approach face severe immunocompetency problems in vivo after engraftment, due to the inadequate in vitro recapitulation of natural thymus microenvironment. Natural mouse Sca1 + cKit + and human CD34 + blood progenitor cells can be induced into CD7 + pre-thymic cells in vitro, which successfully colonize thymi and mature into immunocompetent T cells in vivo.…”

Section: Introductionmentioning

confidence: 99%

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

Guo

Weng

et al. 2019

Cell Res

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Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent stem cells (PSCs) is a central aim in T cell regenerative medicine. To date, preferentially reconstituting T lymphopoiesis in vivo from PSCs remains a practical challenge. Here we documented that synergistic and transient expression of Runx1 and Hoxa9 restricted in the time window of endothelial-tohematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iR9-PSC) in vitro induced preferential generation of engraftable hematopoietic progenitors capable of homing to thymus and developing into mature T cells in primary and secondary immunodeficient recipients. Single-cell transcriptome and functional analyses illustrated the cellular trajectory of T lineage induction from PSCs, unveiling the T-lineage specification determined at as early as hemogenic endothelial cell stage and identifying the bona fide pre-thymic progenitors. The induced T cells distributed normally in central and peripheral lymphoid organs and exhibited abundant TCRαβ repertoire. The regenerative T lymphopoiesis restored immune surveillance in immunodeficient mice. Furthermore, gene-edited iR9-PSCs produced tumor-specific T cells in vivo that effectively eradicated tumor cells. This study provides insight into universal generation of functional and therapeutic T cells from the unlimited and editable PSC source.

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“…The generation of CD8αβ + SP T cells from human pluripotent stem cells without activation-mediated agonist selection has subsequently been demonstrated by the use of 3D murine stromal cell culture 32 . However, physiological positive selection is dependent on the interaction of TCR with self-peptide-MHC complexes, which are uniquely processed and presented by thymic cortical epithelial cells 33 .…”

Section: Discussionmentioning

confidence: 99%

Using Human Induced Pluripotent Stem Cells for the Generation of Tumor Antigen-specific T Cells

Good

Vizcardo

Maeda

et al. 2019

JoVE

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The generation and expansion of functional T cells in vitro can lead to a broad range of clinical applications. One such use is for the treatment of patients with advanced cancer. Adoptive T cell transfer (ACT) of highly enriched tumor antigen-specific T cells has been shown to cause durable regression of metastatic cancer in some patients. However, during expansion, these cells may become exhausted or senescent, limiting their effector function and persistence in vivo. Induced pluripotent stem cell (iPSC) technology may overcome these obstacles by leading to in vitro generation of large numbers of less differentiated tumor antigen-specific T cells. Human iPSC (hiPSC) have the capacity to differentiate into any type of somatic cell, including lymphocytes, which retain the original T cell receptor (TCR) genomic rearrangement when a T cell is used as a starting cell. Therefore, reprogramming of human tumor antigen-specific T cells to hiPSC followed by redifferentiation to T cell lineage has the potential to produce rejuvenated tumor antigen-specific T cells. Described here is a method for generating tumor antigen-specific CD8αβ + single positive (SP) T cells from hiPSC using OP9/DLL1 co-culture system. This method is a powerful tool for in vitro T cell lineage generation and will facilitate the development of in vitro derived T cells for use in regenerative medicine and cell-based therapies.

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Organoid-Induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells

Cited by 170 publications

References 52 publications

Programming for T-lymphocyte fates: modularity and mechanisms

Programming for T-lymphocyte fates: modularity and mechanisms

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

Using Human Induced Pluripotent Stem Cells for the Generation of Tumor Antigen-specific T Cells

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