De novo generation of a functional human thymus from induced pluripotent stem cells

Chhatta, Amiet R.; Cordes, Martijn; Hanegraaf, Maaike; Vloemans, Sandra A.; Cupedo, Tom; Cornelissen, Jan J.; Carlotti, Françoise; Salvatori, Daniela; Pike-Overzet, Karin; Fibbe, Willem E.; Hoeben, Rob C.; Mikkers, Harald; Staal, Frank J. T.

doi:10.1016/j.jaci.2019.05.042

Cited by 27 publications

(25 citation statements)

References 10 publications

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“…Previous studies aiming to generate thymic epithelium from PSCs showed successful differentiation from PSCs to TECs [9][10][11]26 . However, the efficiency of the TEC differentiation was generally low, and Su et al utilized a recombinant transcription factor, HOXA3, and FOXN1 12 .…”

Section: Discussionmentioning

confidence: 99%

Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival

Otsuka

Wada

Tsuji

et al. 2020

Sci Rep

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The thymus plays a significant role in establishing immunological self-tolerance. Previous studies have revealed that host immune reaction to allogeneic transplants could be regulated by thymus transplantation. However, physiological thymus involution hinders the clinical application of these insights. Here, we report an efficient generation of thymic epithelial-like tissue derived from induced pluripotent stem cells (iPSCs) and its potential to regulate immune reaction in allogeneic transplantation. We established an iPSC line which constitutively expresses mouse Foxn1 gene and examined the effect of its expression during in vitro differentiation of thymic epithelial cells (TECs). We found that Foxn1 expression enhances the differentiation induction of cells expressing TEC-related cell surface molecules along with upregulation of endogenous Foxn1. iPSC-derived TECs (iPSC-TECs) generated T cells in nude recipient mice after renal subcapsular transplantation. Moreover, iPSC-TEC transplantation to immuno-competent recipients significantly prolonged the survival of allogeneic skin. Our study provides a novel concept for allogeneic transplantation in the setting of regenerative medicine.

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Section: Discussionmentioning

confidence: 99%

Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival

Otsuka

Wada

Tsuji

et al. 2020

Sci Rep

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“…Direct reprogramming of mouse fibroblasts by enforced FOXN1 expression produced TECs capable of supporting thymocyte development in the mouse (165). In another approach, by adapting protocols which successfully differentiated human embryonic stem cells into thymic epithelium (166,167), patient-derived fibroblasts, induced to revert to a pluripotent stage of induced pluripotent stem cells (iPSCs), could be differentiated into thymic stromal progenitors (149). They could mature only upon in vivo transplantation into athymic nude mice and their capacity to fully instruct human HSC has not yet been demonstrated.…”

Section: Future Directions For Thymus Replacement Therapymentioning

confidence: 99%

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

2021

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Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.

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“…In addition, other technologies in development, such as ESC and iPSC-derived thymii that can output functional naïve T cells, are novel tools for studying human disease etiology. As thymic epithelial cells (iPSC-TEC) (74,75) have the potential to regulate T cell production from progenitors, use of these evolving technologies in combination (gene editing and iPSC-TEC) would allow for studies to dissect how T1D-linked loci, or those linked to other diseases, regulate T cell development. These and other currently advancing technologies will greatly enhance isogenic systems, improving their capacity to model human diseases.…”

Section: Discussionmentioning

confidence: 99%

Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

Armitage

Stimpson

Santostefano

et al. 2021

Preprint

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Type 1 diabetes is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual's collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC, macrophages, EC, and β-cells. Additionally, we also engineered T cell avatars from the same donor to provide an in vitro platform to study genetic influences on these critical cellular interactions. This proof of concept demonstrates the ability to derive an isogenic system from a single donor to study these relevant cell-cell interactions. Our system constitutes an interdisciplinary approach with a controlled environment that provides a proof-of-concept for future studies to determine the role of disease alleles (e.g. IFIH1, PTPN22, SH2B3, TYK2) in regulating cell-cell interactions and cell-specific contributions to the pathogenesis of T1D.

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De novo generation of a functional human thymus from induced pluripotent stem cells

Cited by 27 publications

References 10 publications

Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival

Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

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