Multilineage Potential and Self-Renewal Define an Epithelial Progenitor Cell Population in the Adult Thymus

Wong, Kahlia; Lister, Natalie; Barsanti, Marco; Lim, Joanna; Hammett, Maree Vanessa; Khong, Danika; Siatskas, Christopher; Gray, Daniel H.D.; Boyd, Richard; Chidgey, Ann Patricia

doi:10.1016/j.celrep.2014.07.029

Cited by 146 publications

(204 citation statements)

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“…2 ) were defined as cTEC and mTEC based on the expression of Ly51 and binding of the UEA1 lectin (8,20). mTEC were further divided into mTEC lo and mTEC hi based on low or high expression of CD80 and MHC II molecules (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cell viability was assessed using 7-aminoactinomycin D (BD Biosciences). Isolation of TEC subsets was performed as previously described (8,20 ). For intracellular staining, cell viability was assessed using the Live/Dead fixable blue dead cell stain kit (Invitrogen) and cells were fixed/ permeabilized using the Foxp3 staining buffer Set (eBioscience) and stained with eFluor 660 anti-AIRE Ab (eBioscience).…”

Section: Flow Cytometry Analyses and Cell Sortingmentioning

confidence: 99%

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Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

The Journal of Immunology

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Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non–cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell–cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and -independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus -independent TRA project nonredundant representations of peripheral tissues in the thymus.

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Section: Resultsmentioning

confidence: 99%

Section: Flow Cytometry Analyses and Cell Sortingmentioning

confidence: 99%

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

The Journal of Immunology

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“…c A third possibility for cell-based therapy derives from the in vitro generation of TEPCs from hESCs or by reprogramming fibroblasts by forced FoxN1 expression. Further, the recent characterization of TEPCs in the adult thymus [47] with self-renewal and colony-forming potential, characterized as TEC lo , demonstrated that once activated, this subset could generate cTEC hi and mTEC lo , and indirectly mTEC hi from mTEC lo . This potentially enables a novel strategy for therapeutic thymic regeneration by targeting endogenous TEPCs. …”

Section: Approaches For Thymic Regenerationmentioning

confidence: 99%

“…2). In this way, strategies to manipulate the expression of the critical TEC transcription factor forkhead box n1 (FoxN1) or the activation of TEPCs, recently identified in the adult thymus [47], provide novel strategies to potentially generate more sustained thymus rejuvenation in aging individuals. In addition, protocols have been developed for the directed differentiation of pluripotent stem cells into TEPC in mice and humans [48,49,50,51], for the potential transplantation of de novo generated TEPC.…”

Section: Approaches For Thymic Regenerationmentioning

confidence: 99%

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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“…In CD45 − EpCAM + TECs, MHC II lo , and MHC II hi subsets have been shown to represent the immature and mature TECs, respectively [31][32][33]. We found that rFOXN1 treatment increased the number of both MHC II lo immature and MHC II hi mature TECs 2 days and 1 month after HSCT (Supporting Information Fig.…”

Section: Rfoxn1 Increases the Number Of Total Tecs And Thymocytes In mentioning

confidence: 61%

FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

Song

Zhu

et al. 2016

Eur J Immunol

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A prolonged period of T-cell recovery is the major challenge in hematopoietic stem cell transplantation (HSCT). Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T-cell generation. However, TECs undergo degeneration over time. FOXN1 plays a critical role in TEC development and is required to maintain adult TECs for thymopoiesis. To investigate the potential application of FOXN1, we have cloned and expressed recombinant FOXN1 protein (rFOXN1) that was fused with cellpenetrating peptides. We show here that the rFOXN1 protein can translocate from the cell surface into the cytoplasm and nucleus. Administration of rFOXN1 into both congenic and allogeneic HSCT recipient mice increased the number of TECs, resulting in enhanced thymopoiesis that led to an increased number of functional T cells in the periphery. The increased number of TECs is due to the enhanced survival and proliferation of TECs. Our results suggest that rFOXN1 has the potential to be used in enhancing T-cell regeneration in patients following HSCT.Keywords: FOXN1 r Hematopoietic stem cell transplantation r T-cell generation r Thymic epithelial cells r Thymus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCT is widely used in the treatment of hematopoietic and nonhematopoietic diseases. However, this procedure often suffers from a long period of T-cell recovery, which contributes to increased incidences of infection and relapses of cancer [1][2][3][4][5][6]. Therefore, strategies to enhance T-cell regeneration after HSCT would be greatly beneficial.Correspondence: Dr. Laijun Lai e-mail: laijun.lai@uconn.edu T-cell development occurs primarily in the thymus, and is critically dependent on the thymic microenvironment, in which TECs are the major component. The importance of TECs in thymocyte development has been highlighted by the fact that abnormal TEC development results in immunodeficiency and autoimmunity [7,8]. It is known that TECs undergo a qualitative and quantitative loss over time [8][9][10]. In addition, radiation, chemotherapy, immunosuppressive drugs, and infections, etc. may injure the TECs. Therefore, strategies to restore TECs should lead to enhanced T-cell regeneration and adaptive immunity.FOXN1 is a member of the winged helix/forkhead box transcription factor family. It is generally acknowledged that FOXN1 is a pivotal regulator for TEC development [11][12][13][14][15][16][17][18][19]. Mice homozygous for loss-of-function mutation in FOXN1 display the 'nude' phenotype (FOXN1 nu/nu ), which is characterized by congenital athymia and hairlessness. A mutation in the human FOXN1 gene also results in a nude phenotype [20,21]. FOXN1 is expressed in fetal thymus and postnatal TECs and its expression is progressively down-regulated with aging [15,16,[22][23][24][25]. FOXN1 is required not only for TEC development in fetal thymus, but also for maintenance of the postnatal thymus [15,16,23,24,26]. The reduced expression or indu...

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Multilineage Potential and Self-Renewal Define an Epithelial Progenitor Cell Population in the Adult Thymus

Cited by 146 publications

References 46 publications

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

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

FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

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