Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture

Müller, Susanna; Terszowski, Grzegorz; Blum, Carmen; Haller, Corinne; Anquez, Viviane; Kuschert, Stephen; Carmeliet, Peter; Augustin, Hellmut G.; Rodewald, Hans Reimer

doi:10.1073/pnas.0502752102

Cited by 73 publications

(72 citation statements)

References 35 publications

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“…1D) that could first be ϩ stromal cells also expressed the cortical epithelium marker Ly51 (Fig. 1D); these cells may correspond to the proposed "cortical mesenchyme" population observed in a previous study (48).…”

Section: Thymic Distribution Of Mts-15supporting

confidence: 69%

A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15

Gray

Tull

Ueno

et al. 2007

The Journal of Immunology

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T cell differentiation in the thymus is dependent upon signals from thymic stromal cells. Most studies into the nature of these signals have focused only on the support provided by the thymic epithelium, but there is an emerging view that other stromal cells such as mesenchymal fibroblasts may also be involved. Study of the latter has been hindered by a lack of appropriate markers, particularly those allowing their isolation. In this study, we describe a new surface marker of thymic stroma, MTS-15, and demonstrate its specificity for fibroblasts and a subset of endothelial cells. Coculture experiments showed that the determinant could be transferred between cells. Extensive biochemical analysis demonstrated that the Ag bound by MTS-15 was the glycosphingolipid Forssman determinant, consistent with the distribution observed. Transcriptional analysis of purified MTS-15+ thymic fibroblasts revealed a unique expression profile for a number of chemokines and growth factors important to thymocyte and epithelial cell development. In a model of cyclophosphamide-induced thymic involution and regeneration, fibroblasts were found to expand extensively and express growth factors important to epithelial proliferation and increased T cell production just before thymic regeneration. Overall, this study identifies a useful marker of thymic fibroblasts and highlights this subpopulation as a key player in thymic function by virtue of their support of both thymocytes and epithelial cells.

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Section: Thymic Distribution Of Mts-15supporting

confidence: 69%

A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15

Gray

Tull

Ueno

et al. 2007

The Journal of Immunology

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“…By flow cytometry, we identified two major mesenchymal cell populations in the adult thymus based on expression of Ly51 and gp38: Ly51 int gp38 + and Ly51 hi gp38 2 cells. Although Ly51 + mesenchymal cells are neural crest derived (16,24), to our knowledge, such division within the Ly51 + mesenchyme population has not previously been described. Functionally Ly51 int gp38 + and Ly51 hi gp38 2 cells appear distinct from one another, as only the former subset expressed Aldh1a-1, -2, and -3 and contained within it a population of cells with high ALDH activity.…”

Section: Discussionmentioning

confidence: 77%

“…Consistent with this, mice deficient in FGF-10 or the FGF-10/-7 receptor, FGFR2-IIIb, and mice expressing soluble dominant-negative FGFR2-IIIb display thymus dysgenesis (22,23) and reduced thymic epithelial proliferation (23). Mesenchymal components are found within both the cortex and medulla (16,24), raising the possibility that these cells may be capable of influencing both thymic compartments.…”

mentioning

confidence: 66%

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

Sitnik

Kotarsky

White

et al. 2012

The Journal of Immunology

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The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance of the epithelial compartment of the thymus in T cell development and selection, the potential role of RA in the regulation of thymic cortical and medullary epithelial cell homeostasis has yet to be addressed. In this study, using fetal thymus organ cultures, we demonstrate that endogenous RA signaling promotes thymic epithelial cell (TEC) cell-cycle exit and restricts TEC cellularity preferentially in the cortical TEC compartment. Combined gene expression, biochemical, and functional analyses identified mesenchymal cells as the major source of RA in the embryonic thymus. In reaggregate culture experiments, thymic mesenchyme was required for RA-dependent regulation of TEC expansion, highlighting the importance of mesenchyme-derived RA in modulating TEC turnover. The RA-generating potential of mesenchymal cells was selectively maintained within a discrete Ly51intgp38+ subset of Ly51+ mesenchyme in the adult thymus, suggesting a continual role for mesenchymal cell-derived RA in postnatal TEC homeostasis. These findings identify RA signaling as a novel mechanism by which thymic mesenchyme influences TEC development.

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“…In addition to thymocytes, other non-hematopoietic stromal elements, such as fibroblasts and endothelial cells, and distinct bone marrow-derived dendritic cells (DC) and macrophages also contribute to the final thymic architecture [26]. Thymic mesenchymatous cells also contribute to various structures of the thymus such as capsule or vasculature [27][28][29][30].…”

Section: Embryology Of the Thymusmentioning

confidence: 99%

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

Goffinet¹,

Mottet²,

Kermani³

et al. 2011

IEMAMC

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Abstract:The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction.Keywords: Thymus, growth hormone (GH), insulin-like growth factors (IGFs), HIV, growth hormone deficiency (GHD), Chagas disease. GENERAL INTRODUCTIONThe thymus is now considered as a crucial organ for maintenance of immune system homeostasis and the central lymphoid organ where occurs the generation of self-tolerant and competent naive T cells, as well as self-antigen specific natural Treg cells [1,2]. However, for a long time, the thymus has been regarded as an endocrine gland. In addition, the thymus now appears as a privileged site where the endocrine and immune systems intimately interact.A permanent crosstalk exists between the neuroendocrine and immune systems [3][4][5][6]. In addition to the strong modulation of immunity by glucocorticoids and sexual steroids, other hormones have been more and more involved in immunomodulation. Indeed, the somatotrope GH/IGF-1 axis, as well as prolactin and thyroid hormones [7], were shown to play an important regulatory role in T-cell development [8][9][10].GH is mainly synthesised in the anterior pituitary gland but can also be produced by immune cells [11,12]. GH has several biological actions in the immune system including regulation of thymopoiesis and T-cell development [13]. Nevertheless, it is uneasy to distinguish whether the thymotropic effects of GH are direct or mediated by IGF-1, as most *Address correspondence to this author at the University of Liege Center of Immunoendocrinology (CIL), Institute of Pathology CHU-B23, B-4000 Liege-Sart Tilman, Belgium; Tel: +32 43 66 25 50; Fax: +32 43 66 98 59; E-mail: vgeenen@ulg.ac.be of GH effects are driven by induction of IGF-1 and as IGF-1 has also been described as an endogenous factor in the thymic microenvironment [12]. The evolution of the research field has brought new insights that justify an overview update as some ancie...

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Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture

Cited by 73 publications

References 35 publications

A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15

A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

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