De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids

Zeleniak, Ann E.; Wiegand, Connor; Li, Wen; McCormick, Catherine; Ravikumar, K.; Alavi, Amir; Guan, Huan; Bertera, Suzanne; Lakomy, Robert; Tajima, Asako; Cohen, Henry; Wong, Stéphanie; Balikani, Lamé; Mizerak, Benjamin; Bar‐Joseph, Ziv; Trucco, Massimo; Banerjee, Ipsita; Fan, Yong

doi:10.1038/s41592-022-01583-3

Cited by 25 publications

(12 citation statements)

References 53 publications

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“…123 In the future, such an artificial scaffold may also make it possible to deliver gene-corrected TECs and other stromal cells differentiated from patient-derived induced pluripotent stem cells (iPSCs). While iPSC-based differentiation protocols 124,125 need further optimisation for the generation of functional, mature iTECs able to support thymopoiesis, this is an exciting future avenue for autologous thymus tissue replacement which could reduce the incidence of autoimmune manifestations after thymus transplantation. 5 Currently, these novel tools such as RTOCs and iTECs already play an important role in disease modelling and characterisation of novel thymic stromal cell defects, 19,22,32,33 with direct benefits in the current diagnostic and therapeutic management of athymic patients.…”

Section: Dovepressmentioning

confidence: 99%

Congenital Athymia: Unmet Needs and Practical Guidance

Howley¹,

Davies²,

Kreins³

2023

TCRM

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Inborn errors of thymic stromal cell development and function which are associated with congenital athymia result in lifethreatening immunodeficiency with susceptibility to infections and autoimmunity. Athymic patients can be treated by thymus transplantation using cultured donor thymus tissue. Outcomes in patients treated at Duke University Medical Center and Great Ormond Street Hospital (GOSH) over the past three decades have shown that sufficient T-cell immunity can be recovered to clear and prevent infections, but post-treatment autoimmune manifestations are relatively common. Whilst thymus transplantation offers the chance of long-term survival, significant challenges remain to optimise the outcomes for the patients. In this review, we will discuss unmet needs and offer practical guidance based on the experience of the European Thymus Transplantation programme at GOSH. Newborn screening (NBS) for severe combined immunodeficiency (SCID) and routine use of next-generation sequencing (NGS) platforms have improved early recognition of congenital athymia and increasing numbers of patients are being referred for thymus transplantation. Nevertheless, there remain delays in diagnosis, in particular when the cause is genetically undefined, and treatment accessibility needs to be improved. The majority of athymic patients have syndromic features with acute and chronic complex health issues, requiring life-long multidisciplinary and multicentre collaboration to optimise their medical and social care. Comprehensive follow up after thymus transplantation including monitoring of immunological results, management of co-morbidities and patient and family quality-of-life experience, is vital to understanding long-term outcomes for this rare cohort of patients. Alongside translational research into improving strategies for thymus replacement therapy, patient-focused clinical research will facilitate the design of strategies to improve the overall care for athymic patients.

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Section: Dovepressmentioning

confidence: 99%

Congenital Athymia: Unmet Needs and Practical Guidance

Howley¹,

Davies²,

Kreins³

2023

TCRM

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“…Thus, their presence may challenge the efficiency of the establishment of peripheral tolerance in the recipient. In terms of showing resistance to the de novo generated Tmems in our hu.Thor mice, since we didn’t observe any GVH or HVG once the initial immunosuppression was withheld, we hypothesized that if any Tmem leaves the BM (or any of the lymph nodes in which it resides), the activity of the T regulatory cells, which we demonstrated can be generated by the thymic organoids ( 30 ), may protect against the possible Tmems’ mediated aggression against the graft by controlling or even eliminating them. While our hypothesis is focused on the Treg compartment, we cannot exclude that this peripheral tolerance could be accomplished via other peripheral regulatory pathways that include myeloid-derived suppressor cells (MDSCs), regulatory dendritic cells (DCregs), and regulatory B cells (Bregs), but more detailed research will be needed to elucidate these mechanisms.…”

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confidence: 97%

“…Additionally, they showed expression of specific mTEC ( AIRE and CSN2 ) and cTEC ( CD205 ) lineage markers, indicating the necessary heterogeneity needed to mimic the cellularly complex and spatially regulated thymus gland. At the protein level, surface expression of EpCAM, a widely used marker for defining the TEC population in the thymus, was detected in 70 to 90% of hTEPCs, whereas CD45+, the marker for hematopoietic lineage cells, was largely absent ( 30 ).…”

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confidence: 99%

“… Schematics of hESC/iPSC alginate encapsulation for hTEPC differentiation ( Left ) and of the directed differentiation protocol to thymic epithelial progenitors under alginate encapsulation ( Right ). [Adapted from: A. Zeleniak et al ( 30 )]. …”

mentioning

confidence: 99%

“…The function of the tissue-engineered thymus organoids was also demonstrated in vivo, when human thymus organoids were transplanted under the kidney capsules of NOD.scid.IL2rg null (NSG) immunosuppressed mice. Our model, known as the hu.Thor humanized mouse model (for mice hu manized by th ymus or ganoid transplantation), was able to reject teratomas derived from the allogeneic CC1 iPS cell line while those derived from syngeneic Y1 iPS cells showed robust growth, reflecting both an established functional T cell repertoire and an evident tolerance toward syngeneic tissues ( 30 ).…”

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confidence: 99%

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Central tolerance promoted by cell chimerism

Zeleniak

Trucco

2022

Proc. Natl. Acad. Sci. U.S.A.

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Historically, successful allotransplantation was only achieved by utilizing powerful immunosuppressive drugs that were exposing the patient to severe opportunistic infections. The thymus of the transplant recipient renders such therapy obligatory as it constitutively blocks self-reactive T cells while allowing alloreactive T cells to mature and populate the periphery. In 1992, a follow-up study revealed the presence of donor leukocytes in long-term transplant survivors. The stable persistence of recipient and donor leukocytes in the transplanted patient, referred to as “chimerism”, was considered the reason why in some cases it was even possible to stop immunosuppressive treatment without damaging the transplanted organ. Unfortunately, it quickly became evident that stable, persistent allogeneic chimerism was not easily achievable by design. Recently, a novel approach has been identified to help address this clinical gap in knowledge: Cotransplantation of a donor graft with a thymic organoid populated with donor precursor cells generates stable, long-term chimerism in the recipient. In humanized mice, the implantation of thymic organoids, populated with human donor inducible pluripotent stem cell (iPSC)-derived thymic epithelial cells (TECs) and the same donor CD34+ bone marrow precursors, induces tolerance to human leukocyte antigen (HLA)-matched donor tissues/organs. This technology will allow successful allotransplantation of cells/organs even between Major Histocompatibility Complex (MHC)-noncompatible individuals and allow getting rid of immunosuppressive treatments reducing recipient morbidity.

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Against all odds: The road to success in the development of human immune reconstitution mice

Bin,

Ren,

Zhang

et al. 2024

Anim Models and Exp Med

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The mouse genome has a high degree of homology with the human genome, and its physiological, biochemical, and developmental regulation mechanisms are similar to those of humans; therefore, mice are widely used as experimental animals. However, it is undeniable that interspecies differences between humans and mice can lead to experimental errors. The differences in the immune system have become an important factor limiting current immunological research. The application of immunodeficient mice provides a possible solution to these problems. By transplanting human immune cells or tissues, such as peripheral blood mononuclear cells or hematopoietic stem cells, into immunodeficient mice, a human immune system can be reconstituted in the mouse body, and the engrafted immune cells can elicit human‐specific immune responses. Researchers have been actively exploring the development and differentiation conditions of host recipient animals and grafts in order to achieve better immune reconstitution. Through genetic engineering methods, immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts. From initially only being able to reconstruct single T lymphocyte lineages, it is now possible to reconstruct lymphoid and myeloid cells, providing important research tools for immunology‐related studies. In this review, we compare the differences in immune systems of humans and mice, describe the development history of human immune reconstitution from the perspectives of immunodeficient mice and grafts, and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution, aiming to provide important references for immunological related researches.

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De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids

Cited by 25 publications

References 53 publications

Congenital Athymia: Unmet Needs and Practical Guidance

Congenital Athymia: Unmet Needs and Practical Guidance

Central tolerance promoted by cell chimerism

Against all odds: The road to success in the development of human immune reconstitution mice

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