An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts

Bredenkamp, Nicholas; Ulyanchenko, Svetlana; O’Neill, Kathy E.; Manley, Nancy R.; Vaidya, Harsh Jayesh; Blackburn, C. Clare

doi:10.1038/ncb3023

Cited by 147 publications

(160 citation statements)

References 40 publications

(49 reference statements)

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“…Consistent with the central role of FoxN1 in TEC homeostasis in the adult thymus through the induction of functionality and survival of TEPCs [60,61,62], Bredenkamp et al [63] recently demonstrated that enforced FoxN1 expression alone was sufficient to reprogram mouse embryonic fibroblasts into functional TECs (iTECs). These cells were able to convert ETPs down the thymocyte lineage with CD4 + CD8 + double-positive cells and CD4 + and CD8 + single-positive cells when cocultured in vitro.…”

Section: Approaches For Thymic Regenerationmentioning

confidence: 97%

Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review

2015

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Thymic involution during aging is a major reason for the decreased production of naive T cells and reduced immunity. Alterations within the thymic microenvironment, characterized by the loss of function of thymic epithelial cells (TECs) and fibro-adipogenetic transformation, seem to underlie this process, mainly through declining communication between thymic stromal cells and developing thymocytes. Specifically, the signaling mediated by cytokines and hormones secreted by TECs declines during aging. Many therapies based on the manipulation of growth factors and hormones have succeeded in partially recovering the lymphoid compartment and promoting thymic function. However, considering that aging-induced thymic involution is multifactorial, the thymic reestablishment achieved with treatments that target isolated pathways is incomplete and transitory. Here, we discuss the development of three novel approaches for potentially sustained thymic recovery: the induction of sustained forkhead box N1 expression, the activation of endogenous thymic epithelial progenitor cells (TEPCs), and the generation of TEPCs from pluripotent stem cells. Combined approaches targeting both TECs and lymphoid cells will provide a potentially more effective strategy for sustained rejuvenation of the thymus.

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Section: Approaches For Thymic Regenerationmentioning

confidence: 97%

Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review

2015

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“…Levels of Foxn1 expression have mostly been inferred from analysis of RNA that suggested declining Foxn1 expression to parallel age-dependent thymus involution (4,5,14). Introduction of Foxn1 alone appears to be sufficient to reprogram mouse embryonic fibroblasts into functional TECs (6,7,15), suggesting that Foxn1 is a determining master regulator of TEC development even beginning from non-TECs.…”

mentioning

confidence: 99%

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Rodé

Martins

Küblbeck

et al. 2015

The Journal of Immunology

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The forkhead box N1 (Foxn1) protein is the key regulator of thymic epithelial cell (TEC) development, yet how Foxn1 functions remains largely unknown. All mature TECs arise from Foxn1-expressing progenitors/immature TECs and it is widely assumed that TECs as a whole are defined by Foxn1 expression. However, data on the Foxn1 protein are virtually lacking. In this study, we developed novel tools to visualize Foxn1 protein expression at single-cell resolution. We generated Foxn1 knock-in mice expressing a C-terminal hemagglutinin-tagged Foxn1 protein, and a cytometry-grade monoclonal anti-Foxn1 Ab. We evaluated Foxn1 expression patterns in TEC subsets and its dynamics during normal thymus development, aging, injury, and regeneration. Upon challenges, upregulation of Foxn1 was a common feature of thymus regeneration, but the timing of Foxn1 expression changed and the responding TEC subsets depended on the type of treatment. Whereas dexamethasone and recombinant human fibroblast growth factor 7 promoted expansion of Foxn1+Ly51+CD80− TECs, castration led to expansion of Foxn1+Ly51−CD80+ TECs. Collectively, Foxn1 expression is highly heterogeneous in the normal thymus, with large fractions of Foxn1low or Foxn1− TECs accumulating with age. Furthermore, Foxn1 expression is responsive to perturbations.

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“…In seminal work, the Blackburn lab showed that FoxN1, when expressed at high levels, has the capacity to reprogram mouse embryonic fibroblasts (MEF) to a TEC-like fate (Bredenkamp et al 2014a). After 10 days of FoxN1 expression, MEFs acquired a TEC-like morphology and began expressing genes characteristically expressed in TECs at the fetal stage.…”

Section: Foxn1 and Nude Mice: A Model For Discoverymentioning

confidence: 99%

Artificial Thymus: Recreating Microenvironmental Cues to Direct T Cell Differentiation and Thymic Regeneration

Mohtashami

Shukla

Zandstra

et al. 2016

Synthetic Immunology

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The thymus supports the development and differentiation of T cells, which are a central component of the mammalian adaptive immune system. From entry of hematopoietic progenitor cells into the thymus to their complex maturation sequence into naïve T cells, the role of the thymic microenvironment has been the subject of intense study. A pivotal aspect of this process is the activation of Notch receptors on progenitors by Delta-like (Dll) ligands present on thymic epithelial cells. Thus far, two approaches have been taken to create an artificial thymus, or mimic thymic function. One involves an in vitro cell-based system in which several key components are provided, including Dll and cytokines, to induce and support T cell lineage differentiation. The gold standard approach makes use of a bone marrow-derived cell line (OP9), ectopically expressing Dll (OP9-DL). A related method involves an in vitro cell-free system that provides a similar set of required signaling components. The second approach involves the generation of organized thymic tissue, which can be achieved by direct reprogramming of another cell type or via the differentiation of pluripotent stem cells (PSCs), either by the ectopic expression of the thymic master regulatory gene, FoxN1, in fibroblasts or by inducing the differentiation of PSCs using developmental cues, respectively. These approaches share a similar goal, to generate T cells from different sources of stem cells. However, the former takes advantage of cellular or molecular drivers of T-lineage differentiation, while the latter is focused on creating thymic tissues that would support T cell development.

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An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts

Cited by 147 publications

References 40 publications

Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review

Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Artificial Thymus: Recreating Microenvironmental Cues to Direct T Cell Differentiation and Thymic Regeneration

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