Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation (original) (raw)
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Developing a new paradigm for thymus organogenesis
Nature Reviews Immunology, 2004
The mature thymic epithelium is complex, with two major compartments -the cortex and the medulla -each containing several functionally distinct epithelial-cell types. There is considerable debate as to the embryonic origins of these different thymic epithelial-cell subpopulations. The textbook view is a dual origin, with cortical thymic epithelium arising from the ectoderm and medullary thymic epithelium originating in the endoderm. However, the literature has been divided on this issue since it was first considered. In this review, we discuss recent embryological, functional, genetic and molecular data that collectively support a new model of thymus organogenesis and patterning. STROMA Cells that comprise the nonlymphocytic component of the thymus. LINEAGE Embryonic origin and fate of cells during normal development.
Thymus Inception: Molecular Network in the Early Stages of Thymus Organogenesis
International Journal of Molecular Sciences
The thymus generates central immune tolerance by producing self-restricted and self-tolerant T-cells as a result of interactions between the developing thymocytes and the stromal microenvironment, mainly formed by the thymic epithelial cells. The thymic epithelium derives from the endoderm of the pharyngeal pouches, embryonic structures that rely on environmental cues from the surrounding mesenchyme for its development. Here, we review the most recent advances in our understanding of the molecular mechanisms involved in early thymic organogenesis at stages preceding the expression of the transcription factor Foxn1, the early marker of thymic epithelial cells identity. Foxn1-independent developmental stages, such as the specification of the pharyngeal endoderm, patterning of the pouches, and thymus fate commitment are discussed, with a special focus on epithelial–mesenchymal interactions.
Mechanisms of thymus organogenesis and morphogenesis
Development, 2011
The thymus is the primary organ responsible for generating functional T cells in vertebrates. Although T cell differentiation within the thymus has been an area of intense investigation, the study of thymus organogenesis has made slower progress. The past decade, however, has seen a renewed interest in thymus organogenesis, with the aim of understanding how the thymus develops to form a microenvironment that supports T cell maturation and regeneration. This has prompted modern revisits to classical experiments and has driven additional genetic approaches in mice. These studies are making significant progress in identifying the molecular and cellular mechanisms that control specification, early organogenesis and morphogenesis of the thymus.
Redefining epithelial progenitor potential in the developing thymus
European Journal of Immunology, 2007
Cortical and medullary epithelium represent specialised cell types that play key roles in thymocyte development, including positive and negative selection of the T cell repertoire. While recent evidence shows that these epithelial lineages share a common embryonic origin, the phenotype and possible persistence of such progenitor cells in the thymus at later stages of development remain controversial. Through use of a panel of reagents including the putative progenitor marker Mts24, we set out to redefine the stages in the development of thymic epithelium. In the early embryonic day (E)12 thymus anlagen we find that almost all epithelial cells are uniformly positive for Mts24 expression. In addition, while the thymus at later stages of development was found to contain distinct Mts24 + and Mts24epithelial subsets, thymus grafting experiments show that both Mts24 + and Mts24epithelial subsets share the ability to form organised cortical and medullary thymic microenvironments that support T cell development, a function shown previously to be lost in the Mts24cells by E15 when lower cell doses were used. Our data help to clarify stages in thymic epithelial development and provide important information in relation to currently used markers of epithelial progenitors. See accompanying commentary: http://dx.Abbreviations: E: embryonic day Á EpCAM1: epithelial cell adhesion molecule 1 Á FGFR2: fibroblast growth factor receptor 2
Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors
2016
The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell–restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.
A short primer on early molecular and cellular events in thymus organogenesis and replacement
Swiss medical weekly, 2006
Haematopoietic precursors have to undergo a complex series of maturational steps in the thymus before they exit into the periphery as functional T lymphocytes. Thymic stroma cells, the majority being of epithelial origin, provide the functional partners for the maturational progression along this differentiation pathway. Here we review some of the molecular and cellular mechanisms that account for thymus organogenesis and discuss a strategy to use thymic epithelial precursor cells for the regeneration of the thymic microenvironment.
Thymus formation in uncharted embryonic territories
2022
ABSTRACTThe thymus is a conserved organ among vertebrates, derived from the endoderm of distinct pharyngeal pouches (PP), whose location and number vary in different species. Together with reports of sporadic ectopic thymus locations in mice and humans, this suggests that the potential to make a thymus resides in a broader region of the PP endoderm than previously ascribed.Using the chick-quail chimera system, we explore this hypothesis and test the capacity of non-canonical pouches to participate in thymus formation. We further ask if the local mesenchyme of pharyngeal arches (PA) could also play a role in the regulation of thymus formation.After testing several embryonic tissue associations, we mapped the pharyngeal endoderm regions with thymus potential to the second and third/fourth pharyngeal pouches (2PP and 3/4PP). We further identified mesenchyme regions that regulate this potential to the the 3/4 pharyngeal arches and to the dorsal region of the second arch, with positive a...
2012
The thymus is the primary lymphoid organ where maturation of lymphoid progenitors cells (LPCs) into T-cell occurs. This maturation depends on interactions between the LPCs and thymic epithelium (TE). TE derives from endoderm of the 3 rd and 4 th Pharyngeal Pouches (3/4 PPs) (in chicken) and depends on epithelial-mesenchymal interactions and on LPCs colonization to become functional. Using the quail-chick model, our group showed that distinct mesenchymal tissues are permissive (somatopleure) or non-permissive (limb bud) to 3/4 PPs endoderm specification and early development. In addition, only in the permissive environment the endoderm is colonized by LPCs. In this work, we aimed to identify the molecular cues, namely Notch signaling ligands, involved in TE colonization by LPCs. For that, we used the quail-chick chimeric model. Using immunohistochemistry combined with in situ hybridization techniques we showed that Delta1, as opposed to Delta4, is down-regulated in the endoderm developed in the non-permissive mesenchyme (with no LPCs colonization). Together, these results suggest that mesenchymal-epithelial interactions are important to establish a proper environment to thymus formation and that Delta1 is involved in TE colonization by LPCs. In parallel, we described thymus and parathyroid glands development through the in situ expression analysis of specific transcription factors for each organ (Foxn1 and Gcm2, respectively). We observed that the expression of both transcription factors is maintained from E5 to E13 in the respective developing organs. We then characterized thymocyte populations during thymic organogenesis by flow cytometry analysis. We identified two immature populations, single positive for CD3 or CD8, at early thymic development (<E13), suggesting that these thymocytes may be important in TECs specification into different lineages (cortical and medullary), and subsequent maturation of thymic compartments. With this work, we hope to clarify important events in thymus organogenesis: colonization by LPCs and TECs specification.
Dynamics of Thymus-Colonizing Cells during Human Development
Immunity, 2006
Here, we identify fetal bone marrow (BM)-derived CD34 hi CD45RA hi CD7 + hematopoietic progenitors as thymus-colonizing cells. This population, virtually absent from the fetal liver (FL), emerges in the BM by development weeks 8-9, where it accumulates throughout the second trimester, to finally decline around birth. Based on phenotypic, molecular, and functional criteria, we demonstrate that CD34 hi CD45RA hi CD7 + cells represent the direct precursors of the most immature CD34 hi CD1a 2 fetal thymocytes that follow a similar dynamics pattern during fetal and early postnatal development. Histological analysis of fetal thymuses further reveals that early immigrants predominantly localize in the perivascular areas of the cortex, where they form a lymphostromal complex with thymic epithelial cells (TECs) driving their rapid specification toward the T lineage. Finally, using an ex vivo xenogeneic thymus-colonization assay, we show that BMderived CD34 hi CD45RA hi CD7 + progenitors are selectively recruited into the thymus parenchyma in the absence of exogenous cytokines, where they adopt a definitive T cell fate.