Talk:Endocrine - Thymus Development
What do we know about the structure of human thymic Hassall's corpuscles? A histochemical, immunohistochemical, and electron microscopic study
Ann Anat. 2017 May;211:140-148. doi: 10.1016/j.aanat.2017.02.006. Epub 2017 Mar 6.
Mikušová R1, Mešťanová V2, Polák Š1, Varga I3.
Hassall's corpuscles are the most prominent structures in the human thymus. However, relatively few analyses have been performed to determine their function and cellular origins during development. In this study, we evaluated the cellular microenvironment of human thymic Hassall's corpuscles using histochemistry, immunohistochemistry, and transmission electron microscopy. We examined 95 human thymic tissue samples, which were perioperatively obtained from children undergoing cardiac surgery. To characterize the complex cellular microenvironment of human thymic corpuscles, we used a panel of 14 different antibodies to identify discrete cell types. We also utilized various histochemical methods (PAS reaction, alcian blue staining, alkaline phosphatase and acid phosphatase activity staining, von Kossa staining of calcified particles) and transmission electron microscopy to visualize these structures. Considerable variation in the sizes, shapes, and numbers of Hassall's corpuscles was observed, even amongst children of the same age. Inside the largest Hassall's corpuscles, cystic dilatation with an accumulation of cellular debris was found. These morphological observations might be associated with disruptions in the formation, migration, or differentiation of cardiac neural crest cells, which are essential for heart and thymus development. Immunohistochemical staining and electron microscopy revealed that Hassall's corpuscles resemble other types of stratified squamous epithelia. Most Hassall's corpuscles are heterocellular, consisting of thymic epithelial cells, macrophages, interdigitating dendritic cells, myoid cells, and, occasionally, mast cells and lymphocytes. To explore the potential functions of Hassall's corpuscles, we found that the concentrations of B-lymphocytes and BCL2-positive lymphocytes suggested a role in regulation of lymphopoiesis. We also found that these structures do not originate from the perivascular epithelium as previously proposed, nor could we identify blood or lymph endothelial cells in close proximity. This leaves the origins of Hassall's corpuscles an open question. Copyright © 2017 Elsevier GmbH. All rights reserved.
KEYWORDS: Dendritic cells; Endothelial cells; Epithelial cells; Hassall’s corpuscles; Human thymus; Lymphocytes; Macrophages PMID 28279759 DOI: 10.1016/j.aanat.2017.02.006
Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution
Immunol Rev. 2016 May;271(1):38-55. doi: 10.1111/imr.12412.
Hamazaki Y1, Sekai M1, Minato N1.
The thymus consists of two distinct anatomical regions, the cortex and the medulla; medullary thymic epithelial cells (mTECs) play a crucial role in establishing central T-cell tolerance for self-antigens. Although the understanding of mTEC development in thymic organogenesis as well as the regulation of their differentiation and maturation has improved, the mechanisms of postnatal maintenance remain poorly understood. This issue has a central importance in immune homeostasis and physiological thymic involution as well as autoimmune disorders in various clinicopathological settings. Recently, several reports have demonstrated the existence of TEC stem or progenitor cells in the postnatal thymus, which are either bipotent or unipotent. We identified stem cells specified for mTEC-lineage that are generated in the thymic ontogeny and may sustain mTEC regeneration and lifelong central T-cell self-tolerance. This finding suggested that the thymic medulla is maintained autonomously by its own stem cells. Although several issues, including the relationship with other putative TEC stem/progenitors, remain unclear, further examination of mTEC stem cells (mTECSCs) and their regulatory mechanisms may contribute to the understanding of postnatal immune homeostasis. Possible relationships between decline of mTECSC activity and early thymic involution as well as various autoimmune disorders are discussed.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
KEYWORDS: central tolerance; medullary thymic epithelial stem cells; thymic epithelial cells; thymic epithelial stem cells; thymic involution; thymus PMID 27088906 DOI: 10.1111/imr.12412
Structure and function of the thymic microenvironment
Front Biosci. 2011 Jun 1;17:2461-77.
Manley NR, Richie ER, Blackburn CC, Condie BG, Sage J. Source Department of Genetics, Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA. firstname.lastname@example.org Abstract Organs are more than the sum of their component parts--functional competence requires that these parts not only be present in the appropriate proportions, but also be arranged and function together in specific ways. The thymus is an excellent example of the connection between cellular organization and organ function. Unlike more familiar organs, such as lung or kidney, the thymus is not organized into easily identifiable structures such as tubes and ordered cell layers, but instead is a complex meshwork of microenvironments through which T cell progenitors migrate, receiving signals that instruct them to differentiate, proliferate, or die. Proper thymic organization is essential to the optimal production of a functional T cell repertoire. During aging, the thymus undergoes involution, largely due to degradation of the TEC microenvironmental compartment, which then fails to support optimal thymocyte development resulting in reduced output of naive T cells. This review will summarize the current state of understanding of the composition and organization of thymic microenvironments and the mechanisms that promote their proper development and function.
Wnt4 and LAP2alpha as pacemakers of thymic epithelial senescence
Kvell K, Varecza Z, Bartis D, Hesse S, Parnell S, Anderson G, Jenkinson EJ, Pongracz JE. PLoS One. 2010 May 18;5(5):e10701. PMID: 20502698
Foxn1 is essential for vascularization of the murine thymus anlage
Mori K, Itoi M, Tsukamoto N, Amagai T. Cell Immunol. 2010;260(2):66-9. Epub . PMID: 19853842
Lessons from thymic epithelial heterogeneity: FoxN1 and tissue-restricted gene expression by extrathymic, endodermally derived epithelium
Dooley J, Erickson M, Farr AG. J Immunol. 2009 Oct 15;183(8):5042-9. Epub 2009 Sep 28. PMID 19786540
A roadmap for thymic epithelial cell development
Anderson G, Jenkinson EJ, Rodewald HR. Eur J Immunol. 2009 Jul;39(7):1694-9. Review. PMID 19582736
Foxa2 regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo
Burtscher I, Lickert H. Development. 2009 Mar;136(6):1029-38. PMID 19234065
Characterization of the thymic IL-7 niche in vivo
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1512-7. Epub 2009 Jan 21.
Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VS, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP.
Cytokines and Lymphoid Development Unit, Lymphocyte Development Unit, Plate-Forme Technologique Centre d'Ingénierie Génétique Murine, and Laboratory of Lymphoid Tissue Development, Institut Pasteur, Paris, France. Abstract The thymus represents the "cradle" for T cell development, with thymic stroma providing multiple soluble and membrane cues to developing thymocytes. Although IL-7 is recognized as an essential factor for thymopoiesis, the "environmental niche" of thymic IL-7 activity remains poorly characterized in vivo. Using bacterial artificial chromosome transgenic mice in which YFP is under control of IL-7 promoter, we identify a subset of thymic epithelial cells (TECs) that co-express YFP and high levels of Il7 transcripts (IL-7(hi) cells). IL-7(hi) TECs arise during early fetal development, persist throughout life, and co-express homeostatic chemokines (Ccl19, Ccl25, Cxcl12) and cytokines (Il15) that are critical for normal thymopoiesis. In the adult thymus, IL-7(hi) cells localize to the cortico-medullary junction and display traits of both cortical and medullary TECs. Interestingly, the frequency of IL-7(hi) cells decreases with age, suggesting a mechanism for the age-related thymic involution that is associated with declining IL-7 levels. Our temporal-spatial analysis of IL-7-producing cells in the thymus in vivo suggests that thymic IL-7 levels are dynamically regulated under distinct physiological conditions. This IL-7 reporter mouse provides a valuable tool to further dissect the mechanisms that govern thymic IL-7 expression in vivo.
On the role of Eph signalling in thymus histogenesis; EphB2/B3 and the organizing of the thymic epithelial network
García-Ceca J, Jiménez E, Alfaro D, Cejalvo T, Chumley MJ, Henkemeyer M, Muñoz JJ, Zapata AG. Int J Dev Biol. 2009;53(7):971-82.
PMID 19598115 http://www.ncbi.nlm.nih.gov/pubmed/19598115
In the current study, we extend our own previous results on the thymocyte phenotype of EphB2 and/or EphB3 deficient mice by analyzing the phenotype and the histological organization of their thymic epithelial stroma. All studied adult EphB-deficient thymi showed profound alterations with respect to the wild-type (WT) ones. Each mutant exhibited a specific phenotype, but also showed common features including occurrence of K5+K8+MTS10+ immature medullary epithelial cells, numerous K5-K8-MTS20+ cells and K5+K8+ cells in the thymic cortex and cortical and medullary K5-K8- areas devoid of epithelial cell markers. In addition, comparative analysis of WT and EphB-deficient embryonic and newborn thymi demonstrated that the observed adult phenotype was a consequence of the gradual accumulation of early phenotypic and morphological defects, becoming more severe at the end of embryonic life and in newborn animals. Together, these results confirm a role for EphB2 and EphB3 in thymus morphogenesis. The obtained data are discussed from the point of view of the recognized role played by these two Ephs in the homeostasis of other epithelia and their possible relationships with molecules known to be involved in thymic epithelial cell development.
Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells
Depreter MG, Blair NF, Gaskell TL, Nowell CS, Davern K, Pagliocca A, Stenhouse FH, Farley AM, Fraser A, Vrana J, Robertson K, Morahan G, Tomlinson SR, Blackburn CC. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):961-6. Epub 2008 Jan 14.
The thymus is essential for a functional immune system, because the thymic stroma uniquely supports T lymphocyte development. We have previously identified the epithelial progenitor population from which the thymus arises and demonstrated its ability to generate an organized functional thymus upon transplantation. These thymic epithelial progenitor cells (TEPC) are defined by surface determinants recognized by the mAbs MTS20 and MTS24, which were also recently shown to identify keratinocyte progenitor cells in the skin. However, the biochemical nature of the MTS20 and MTS24 determinants has remained unknown. Here we show, via expression profiling of fetal mouse TEPC and their differentiated progeny and subsequent analyses, that both MTS20 and MTS24 specifically bind an orphan protein of unknown function, Placenta-expressed transcript (Plet)-1. In the postgastrulation embryo, Plet-1 expression is highly restricted to the developing pharyngeal endoderm and mesonephros until day 11.5 of embryogenesis, consistent with the MTS20 and MTS24 staining pattern; both MTS20 and MTS24 specifically bind cell lines transfected with Plet-1; and antibodies to Plet-1 recapitulate MTS20/24 staining. In adult tissues, we demonstrate expression in a number of sites, including mammary and prostate epithelia and in the pancreas, where Plet-1 is specifically expressed by the major duct epithelium, providing a specific cell surface marker for this putative reservoir of pancreatic progenitor/stem cells. Plet-1 will thus provide an invaluable tool for genetic analysis of the lineage relationships and molecular mechanisms operating in the development, homeostasis, and injury in several organ/tissue systems.
PMID: 18195351 http://www.ncbi.nlm.nih.gov/pubmed/18195351
An epithelial progenitor pool regulates thymus growth
Jenkinson WE, Bacon A, White AJ, Anderson G, Jenkinson EJ. J Immunol. 2008 Nov 1;181(9):6101-8.
PMID: 18941199 http://www.ncbi.nlm.nih.gov/pubmed/18941199
Thymic epithelium provides an essential cellular substrate for T cell development and selection. Gradual age-associated thymic atrophy leads to a reduction in functional thymic tissue and a decline in de novo T cell generation. Development of strategies tailored toward regeneration of thymic tissue provides an important possibility to improve immune function in elderly individuals and increase the capacity for immune recovery in patients having undergone bone marrow transfer following immunoablative therapies. In this study we show that restriction of the size of the functional thymic epithelial progenitor pool affects the number of mature thymic epithelial cells. Using an embryo fusion chimera-based approach, we demonstrate a reduction in the total number of both embryonic and adult thymic epithelium, which relates to the initial size of the progenitor cell pool. The inability of thymic epithelial progenitor cells to undergo sufficient compensatory proliferation to rescue the deficit in progenitor numbers suggests that in addition to extrinsic regulation of thymus growth by provision of growth factors, intrinsic factors such as a proliferative restriction of thymic epithelial progenitors and availability of progenitor cell niches may limit thymic epithelial recovery. Collectively, our data demonstrate an important level of regulation of thymic growth and recovery at the thymic epithelial progenitor level, providing an important consideration for developing methods targeted toward inducing thymic regeneration.
Rodewald HR. Annu Rev Immunol. 2008;26:355-88. Review. PMID: 18304000 http://www.ncbi.nlm.nih.gov/pubmed/18304000
The epithelial architecture of the thymus fosters growth, differentiation, and T cell receptor repertoire selection of large numbers of immature T cells that continuously feed the mature peripheral T cell pool. Failure to build or to maintain a proper thymus structure can lead to defects ranging from immunodeficiency to autoimmunity. There has been long-standing interest in unraveling the cellular and molecular basis of thymus organogenesis. Earlier studies gave important morphological clues on thymus development. More recent cell biological and genetic approaches yielded new and conclusive insights regarding the germ layer origin of the epithelium and the composition of the medulla as a mosaic of clonally derived islets. The existence of epithelial progenitors common for cortex and medulla with the capacity for forming functional thymus after birth has been uncovered. In addition to the thymus in the chest, mice can have a cervical thymus that is small, but functional, and produces T cells only after birth. It will be important to elucidate the pathways from putative thymus stem cells to mature thymus epithelial cells, and the properties and regulation of these pathways from ontogeny to thymus involution.
DiGeorge syndrome or Velocardiofacial syndrome (Shrprintzen Syndrome)
Obituary of Dr. Angelo Di George
Dr. Angelo M. DiGeorge a world renowned physician and pediatric endocrinologist, died at age of 88 years, on October 11, 2009 of kidney failure at his home in Philadelphia.
Dr. DiGeorge first gained international recognition in the mid-1960's for his ground breaking discovery of a disorder characterized by congenital absence of the thymus and associated abnormalities. This birth defect in now-a-day referred to as DiGeorge syndrome or Velocardiofacial syndrome (Shrprintzen Syndrome) or chromosome 22q11.2 deletion syndrome, since the majority of affected individuals have a distinct part of the long arm of this chromosome missing. DiGeorge syndrome includes a pattern of more than 200 different defects, including hypoplastic thymus and parathyroid glands, conotruncal heart defects, and a characteristic facial appearance. Velocardiofacial syndrome is marked by the association of congenital conotruncal heart defects, cleft palate or velar insufficiency, facial anomalies and learning difficulties. It is now accepted that these two syndromes represent the different expression of a unique disorder manifesting at different stages of life. DiGeorge Syndrome is one of the most common genetic disorders known, occurring in about one every 4,000 livebirths. The DiGeorge's original 1965 paper reporting this anomaly has been quoted more than 500,000 times worldwide and the Google search yields more than 700,000 citations. During his long professional career, DiGeorge was one of the key figures who contributed to transform the Philadelphia St.Christopher's Hospital for Children from a small community hospital into a nationally prominent medical institution. DiGeorge has authored more than 230 medical papers, abstracts and text book chapters and he has been an invited guest lecturer around the world.
Thymus medulla consisting of epithelial islets each derived from a single progenitor
Nature. 2001 Dec 13;414(6865):763-8.
Rodewald HR1, Paul S, Haller C, Bluethmann H, Blum C.
The thymus is organized into medullary and cortical zones that support distinct stages of T-cell development. The formation of medulla and cortex compartments is thought to occur through invagination of an endodermal epithelial sheet into an ectodermal one at the third pharyngeal pouch and cleft, respectively. Epithelial stem/progenitor cells have been proposed to be involved in thymus development, but evidence for their existence has been elusive. We have constructed chimaeric mice by injecting embryonic stem (ES) cells into blastocysts using ES cells and blastocysts differing in their major histocompatibility complex (MHC) type. Here we show that the MHC class-II-positive medullary epithelium in these chimaeras is composed of cell clusters, most of which derive from either embryonic stem cell or blastocyst, but not mixed, origin. Thus, the medulla comprises individual epithelial 'islets' each arising from a single progenitor. One thymic lobe has about 300 medullary areas that originate from as few as 900 progenitors. Islet formation can be recapitulated after implantation of 'reaggregated fetal thymic organs' into mice, which shows that medullary 'stem' cells retain their potential until at least day 16.5 in fetal development. Thus, medulla-cortex compartmentalization is established by formation of medullary islets from single progenitors. PMID 11742403 DOI: 10.1038/414763a