DKK1 Mediated Inhibition of Wnt Signaling in Postnatal Mice Leads to Loss of TEC Progenitors and Thymic Degeneration

Osada, Masako; Jardine, Logan; Misir, R.; Andl, Thomas; Millar, Sarah E.; Pezzano, Mark

doi:10.1371/journal.pone.0009062

Cited by 58 publications

(60 citation statements)

References 92 publications

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“…Consistent with the latter hypothesis, decrease in the mTEC/cTEC ratio is observed in normal age-related thymic involution in wild-type mice and in pathologic thymic atrophy in several mutant mice. 13,14,31 In conclusion, we show here that Wnt4 regulates the expansion of both immature thymocytes and TECs with the net effect of increasing total cellularity in the fetal as well as early postnatal and adult thymus. Together with our previous report on the role of Wnt4 in thymic recovery post-HCT, 23 our data suggest that Wnt4, or its downstream effectors, would make very interesting candidates for countering thymic insufficiency and atrophy.…”

Section: Wnt4 In Fetal and Postnatal Thymopoiesis 5171supporting

confidence: 52%

“…9,10 Although thymic epithelial cells (TECs) provide growth factors and signals that will promote migration and T lineage commitment to the developing lymphocytes, the presence of lymphocytes is also necessary for the differentiation and functional maturation of TECs. 11,12 Postnatal disruption of TECs results in thymic atrophy, 13,14 whereas restoration of thymocyte development can reestablish TEC architecture in cases where the defect was thymocyte intrinsic. 15,16 Several studies have shown the importance of proper regulation of Wnt signaling during T-cell development.…”

Section: Introductionmentioning

confidence: 99%

“…Inducible overexpression of the Wnt inhibitor Dkk1 in TECs resulted in the loss of keratin (K)8 ϩ K5 ϩ (progenitor) TECs and reversible thymic involution. 14 Conversely, the Wnt antagonist Kremen was shown to be necessary for the establishment of normal TEC numbers during thymic organogenesis. 19 Interestingly, stabilization of ␤-catenin in epithelial cells prevented thymic development, 20,21 despite the fact that canonical Wnt signaling, and in particular Wnt4, have been suggested to induce FoxN1 expression.…”

Section: Introductionmentioning

confidence: 99%

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Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

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Section: Wnt4 In Fetal and Postnatal Thymopoiesis 5171supporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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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: 71%

“…These results suggest that FOXN1 induced mTEC proliferation is due, at least in part, to the enhanced expression of cyclin D1. Whether cyclin D1 and p53 are the directly or indirectly downstream target genes remains to be determined.In addition to an increased number of mature TECs, rFOXN1 treatment also increased the number of MHC II lo immature TECs.Several investigators have also shown that, in addition to maintain existing TECs, FOXN1 also regulates TEC progenitors [15,16,18,27,31], which may also contribute to the increased number of TECs. The number of ETPs was also significantly increased after rFOXN1 treatment.…”

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confidence: 99%

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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Characterization of Lgr5‐positive epithelial cells in the murine thymus

et al. 2013

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Leucine-rich repeat-containing G protein-coupled receptor (Lgr)5 is a marker for epithelial stem cells in the adult intestine of mice. Lgr5 transcripts have also been detected in the developing murine thymus, leading to speculation that Lgr5 is a marker for the longsought stem cell of the thymus. To address the nature of the Lgr5-expressing thymic epithelial cells (TECs), we used Lgr5-GFP reporter mice. We show that epithelial cells expressing Lgr5 protein are present in the fetal thymus during a specific developmental window yet are no longer detectable at birth. To analyze the function of the Lgr5 protein during thymus development, we generated Lgr5 −/− mice. These experiments unequivocally show that thymus development is not perturbed in the absence of Lgr5, that all TEC subsets develop in Lgr5 −/− mice and that T cells are produced in the expected ratios. Finally, by using an inducible lineage tracing system to track the progeny of Lgr5 + fetal TECs in vivo, we demonstrated that Lgr5 + fetal TECs have no detectable progeny in the later fetal thymus. In sum, we show that presence of the Lgr5 protein is not a prerequisite for proper thymus organogenesis. Keywords:Fetal thymus r Lgr5 r Lineage tracing r Thymic epithelial cells IntroductionThymic epithelial cells (TECs) form a 3D network that is essential for the proper proliferation, differentiation, and selection of developing thymocytes. Epithelial derived factors include growth factors, differentiation signals, and self-antigens expressed via MHC class I (MHCI) and MHC class II (MHCII) (reviewed in [1]). Presentation of self-antigens on TECs [2-5], the exact timing, affinity, and cofactors for the physiological contact between TECs and developing T cells (reviewed in [6]) is fundamental for proper T-cell development.The murine thymus originates from the third pharyngeal pouch at day E9.5 of embryonic development and is solely derived from the endoderm [7]. Specification of the thymus involves the sequential upregulation of important transcription factors (Hoxa3, Eya1, Rae2, chordin, and BMP; (reviewed in [8]) eventually leading to the expression of the thymic-specific transcription Correspondence: Prof. Jan J. Cornelissen e-mail: J.Cornelissen@erasmusmc.nl factor Foxn1 [9,10]. From E11.5 onwards, the first precursor T cells migrate into the thymic anlage and noncanonical NF-κB signaling becomes important for full differentiation of the medullary microenvironment, culminating in the upregulation of autoimmune regulator (Aire) [11][12][13] that enables medullary TECs to express self-antigens [2,3]. In the adult thymus cross-talk remains important, as the process of differentiation but also maintenance of medullary TECs, via ligation of RANK and CD40 by ligands expressed on thymocytes [11,12,14].Mature cortical and medullary TEC originate from a common thymic epithelial progenitor cell (TEPC) [15,16]. Although full differentiation of mature TECs from a clonal precursor population has been demonstrated, the precise phenotypical characterization of that precursor...

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DKK1 Mediated Inhibition of Wnt Signaling in Postnatal Mice Leads to Loss of TEC Progenitors and Thymic Degeneration

Cited by 58 publications

References 92 publications

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

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

Characterization of Lgr5‐positive epithelial cells in the murine thymus

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