Human stem cell-derived thymic epithelial cells enhance human T-cell development in a xenogeneic thymus

Gras-Peña, Rafael; Danzl, Nichole; Khosravi‐Maharlooei, Mohsen; Campbell, Sammy C.; Ruiz, Amanda; Parks, Christopher A.; Savage, William; Hölzl, Markus A.; Chatterjee, Debanjana; Sykes, Megan

doi:10.1016/j.jaci.2021.09.038

Cited by 15 publications

(28 citation statements)

References 79 publications

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“…Hence, the fine temporal modulation of the Hedgehog-specific pathways may be key to trigger a proper differentiation towards pharyngeal endoderm. Other examples of temporal modulations are also observed with the inhibition of BMP through Noggin between day 15 to day 21 followed by a more classical activation of BMP4 from day 21, resulting in a significant 10-fold increase of PAX9 expression ( 133 ). Another key insight from this study was the addition of FGF8b during endoderm anteriorization at day 4.5 which results in a 5-fold increase of FOXN1 expression.…”

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 98%

“…and Gras-peña et al. optimized the differentiation protocols, notably by modulating temporal Hedgehog signaling ( 132 , 133 ) ( Figure 3 ). Interestingly, both protocols include Hedgehog activation during the step of pharyngeal endoderm induction, contrary to what was done in a previous report ( 126 ).…”

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 99%

“…Heterogeneity of the directed differentiation products is also a crucial stake for clinical applications since undifferentiated iPSc can lead to teratoma formation after transplantation. Purification strategies and treatment by selective anti-iPSc molecules such as YM155 ( 133 ) are promising approaches to mitigate this risk. This differentiation heterogeneity could also counter-intuitively positively affect the generation of iPSc-derived TECs.…”

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 99%

“…Finally, a long-term culture system accurately reproducing in vivo thymic microenvironment still needs to be developed. Although TECs derived from iPSc can be maintained in classical 2D culture for up to 30 days ( 133 ), a culture system closer to the 3D sponge-like structure of the thymic stroma could significantly improve TEC differentiation and viability.…”

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 99%

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Differentiation of Pluripotent Stem Cells Into Thymic Epithelial Cells and Generation of Thymic Organoids: Applications for Therapeutic Strategies Against APECED

Provin

Giraud

2022

Front. Immunol.

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The thymus is a primary lymphoid organ essential for the induction of central immune tolerance. Maturing T cells undergo several steps of expansion and selection mediated by thymic epithelial cells (TECs). In APECED and other congenital pathologies, a deficiency in genes that regulate TEC development or their ability to select non auto-reactive thymocytes results in a defective immune balance, and consequently in a general autoimmune syndrome. Restoration of thymic function is thus crucial for the emergence of curative treatments. The last decade has seen remarkable progress in both gene editing and pluripotent stem cell differentiation, with the emergence of CRISPR-based gene correction, the trivialization of reprogramming of somatic cells to induced pluripotent stem cells (iPSc) and their subsequent differentiation into multiple cellular fates. The combination of these two approaches has paved the way to the generation of genetically corrected thymic organoids and their use to control thymic genetic pathologies affecting self-tolerance. Here we review the recent advances in differentiation of iPSc into TECs and the ability of the latter to support a proper and efficient maturation of thymocytes into functional and non-autoreactive T cells. A special focus is given on thymus organogenesis and pathway modulation during iPSc differentiation, on the impact of the 2/3D structure on the generated TECs, and on perspectives for therapeutic strategies in APECED based on patient-derived iPSc corrected for AIRE gene mutations.

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Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 98%

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 99%

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 99%

Section: Differentiation Of Pluripotent Stem Cells Into the Thymic Li...mentioning

confidence: 99%

See 2 more Smart Citations

Differentiation of Pluripotent Stem Cells Into Thymic Epithelial Cells and Generation of Thymic Organoids: Applications for Therapeutic Strategies Against APECED

Provin

Giraud

2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…In vitro differentiation methods have been developed to produce thymic epithelial progenitors (TEPs) from human embryonic stem cells (hESCs) [ [110] , [111] , [112] , [113] , [114] ] and iPSCs [ 113 , [115] , [116] , [117] ] (SC-TEPs). These protocols recapitulate the multi-step development of the thymus and can generate immature SC-TEPs within ∼2 weeks (reviewed in [ 118 , 119 ]).…”

Section: Thymic Epithelial Cells (Tecs)mentioning

confidence: 99%