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.
Hematopoietic stem cells (HSCs) derived from birth through adult possess differing differentiation potential for T or B cell fate in the thymus; neonatal bone marrow (BM) cells also have a higher ...potential for B cell production in BM compared to adult HSCs. We hypothesized that this hematopoietic-intrinsic B potential might also regulate B cell development in the thymus during ontogeny.
Foxn1lacZ mutant mice are a model in which down regulation of a thymic epithelial cell (TEC) specific transcription factor beginning one week postnatal causes a dramatic reduction of thymocytes production. In this study, we found that while T cells were decreased, the frequency of thymic B cells was greatly increased in these mutants in the perinatal period. We used this model to characterize the mechanisms in the thymus controlling B cell development.
Foxn1lacZ mutants, T cell committed intrathymic progenitors (DN1a,b) were progressively reduced beginning one week after birth, while thymic B cells peaked at 3-4 weeks with pre-B-II progenitor phenotype, and originated in the thymus. Heterochronic chimeras showed that the capacity for thymic B cell production was due to a combination of higher B potential of neonatal HSCs, combined with a thymic microenvironment deficiency including reduction of DL4 and increase of IL-7 that promoted B cell fate.
Our findings indicate that the capacity and time course for thymic B-cell production are primarily controlled by the hematopoietic-intrinsic potential for B cells themselves during ontogeny, but that signals from TECs microenvironment also influence the frequency and differentiation potential of B cell development in the thymus.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The postnatal thymus is the primary source of T cells in vertebrates, and many if not all stages of thymocyte development require interactions with thymic epithelial cells (TECs). The Foxn1 gene is a ...key regulator of TEC differentiation, and is required for multiple aspects of fetal TEC differentiation. Foxn1 is also expressed in the postnatal thymus, but its function after birth is unknown. We generated a Foxn1 allele with normal fetal expression and thymus development, but decreased expression in the postnatal thymus. This down-regulation causes rapid thymic compartment degeneration and reduced T-cell production. TEC subsets that express higher Foxn1 levels are most sensitive to its down-regulation, in particular MHCIIhiUEA-1hi medullary TECs. The requirement for Foxn1 is extremely dosage sensitive, with small changes in Foxn1 levels having large effects on thymus phenotypes. Our results provide the first evidence that Foxn1 is required to maintain the postnatal thymus. Furthermore, the similarities of this phenotype to accelerated aging-related thymic involution support the possibility that changes in Foxn1 expression in TECs during aging contribute to the mechanism of involution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The postnatal thymus is an efficient microenvironment for T cell specification and differentiation. B cells are also present in the thymus and have been recently shown to impact T cell selection, ...however, the mechanisms controlling B cell development in the thymus are largely unknown. In Foxn1lacZ mutant mice, down-regulation of Foxn1 expression in thymic epithelial cells beginning 1 week after birth caused a dramatic reduction of T progenitors and an increase of B cell progenitors. This time point is coincident with the switch from fetal to adult-type hematopoietic stem cells (HSCs), which is regulated by the Lin28-Let7 system. We hypothesize that the thymic environment might regulate this process to suppress fetal-type B cell development in the thymus. In this study we show that in the Foxn1lacZ thymus, although the down-regulation of Lin28 in thymocytes was normal, up-regulation of Let-7 was impaired. The failure to up-regulate Let-7 caused a transient increase of Arid3a in B precursors, which is known to promote fetal-type B cell fate. Over-expression of Lin28a in HSCs also reduced Let-7 and promoted Arid3a expression in BM and thymic B progenitors, increasing B cell production in the thymus. The level of Let-7 in thymic B progenitors was up regulated by in vitro co-culture with IL15, Vitamin-D3, and retinoic acid, thus down-regulating Arid3a to promote B cell differentiation. All of these signals were produced in thymic epithelial cells (TECs) related to Let-7 expression in thymic B progenitors, and down-regulated in Foxn1lacZ mutants. Our data show that signals provided by TEC control thymic B cell development by up-regulating Let-7, suppressing Arid3a expression in intrathymic progenitor B cells to limit their proliferation during the neonatal to adult transition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Glasgow Outcome Scale-Extended (GOSE) has become one of the most widely used outcome instruments to assess global disability and recovery after traumatic brain injury. Achieving consistency in ...the application of the assessment remains a challenge, particularly in multi-center studies involving many assessors. We present a manual for the GOSE interview that is designed to support both single- and multi-center studies and promote inter-rater agreement. Many patients fall clearly into a particular category; however, patients may have outcomes that are on the borderline between adjacent categories, and cases can present other challenges for assessment. The Manual includes the general principles of assessment, advice on administering each section of the GOSE interview, and guidance on "borderline" and "difficult" cases. Finally, we discuss the properties of the GOSE, including strengths and limitations, and outline recommendations for assessor training, accreditation, and monitoring.
Embryology of the Parathyroid Glands Peissig, Kristen; Condie, Brian G; Manley, Nancy R
Endocrinology and metabolism clinics of North America,
12/2018, Volume:
47, Issue:
4
Journal Article
Peer reviewed
Open access
The parathyroid glands are essential for regulating calcium homeostasis in the body. The genetic programs that control parathyroid fate specification, morphogenesis, differentiation, and survival are ...only beginning to be delineated, but are all centered around a key transcription factor, GCM2. Mutations in the Gcm2 gene as well as in several other genes involved in parathyroid organogenesis have been found to cause parathyroid disorders in humans. Therefore, understanding the normal development of the parathyroid will provide insight into the origins of parathyroid disorders.
There is an accumulating body of evidence that a decline in immune function with age is common to most if not all vertebrates. For instance, age-associated thymic involution seems to occur in all ...species that possess a thymus, indicating that this process is evolutionary ancient and conserved. The precise mechanisms regulating immunosenescence remain to be resolved, but much of what we do know is consistent with modern evolutionary theory. In this review, we assess our current knowledge from an evolutionary perspective on the occurrence of immunosenescence, we show that life history trade-offs play a key role and we highlight the possible advantages of the age-related decline in thymic function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Thymic epithelial cells (TECs) are a critical functional component of the thymus's ability to generate T cells for the adaptive immune system in vertebrates. However, no in vitro system for studying ...TEC function exists. Overexpressing the transcription factor FOXN1 initiates transdifferentiation of fibroblasts into TEC-like cells (iTECs) that support T cell differentiation in culture or after transplant. In this study, we characterized iTEC programming at the cellular and molecular level to determine how it proceeds and identified mechanisms that can be targeted for improving this process. These data showed that iTEC programming consisted of discrete gene expression changes that differed early and late in the process, and that iTECs upregulated markers of both cortical and medullary TEC (cTEC and mTEC) lineages. We demonstrated that promoting proliferation enhanced iTEC generation, and that Notch inhibition allowed induction of mTEC differentiation. Finally, we showed that MHCII expression was the major difference between iTECs and fetal TECs. MHCII expression was improved by co-culturing iTECs with fetal double-positive T-cells. This study supports future efforts to improve iTEC generation for both research and translational uses.
Thymic epithelial cells (TECs) are essential for T cell development in the thymus, yet the mechanisms governing their differentiation are not well understood. Lin28, known for its roles in embryonic ...development, stem cell pluripotency, and regulating cell proliferation and differentiation, is expressed in endodermal epithelial cells during embryogenesis and persists in adult epithelia, implying postnatal functions. However, the detailed expression and function of Lin28 in TECs remain unknown. In this study, we examined the expression patterns of
and its target
in fetal and postnatal TECs and discovered opposing expression patterns during postnatal thymic growth, which correlated with FOXN1 and MHCII expression. Specifically,
showed high expression in MHCII
TECs, whereas
was expressed in MHCII
TECs. Deletion of
and
specifically in TECs resulted in reduced MHCII expression and overall TEC numbers. Conversely, overexpression of
increased total TEC and thymocyte numbers by promoting the proliferation of MHCII
TECs. Additionally, our data strongly suggest that
and
expression is reliant on FOXN1 to some extent. These findings suggest a critical role for Lin28 in regulating the development and differentiation of TECs by modulating MHCII expression and TEC proliferation throughout thymic ontogeny and involution. Our study provides insights into the mechanisms underlying TEC differentiation and highlights the significance of Lin28 in orchestrating these processes.
Highlights ► Hypoxic niches are critical for sustaining bone marrow stem cell lymphopoiesis. ► ROS and IL-6 accelerate bone marrow lymphoid senescence with aging. ► HIF-1α and PPARγ2 modulate bone ...marrow lymphopoiesis with aging. ► Loss of stromal-thymocyte cross-talk contributes to thymic involution with aging. ► Intrathymic changes in Foxn1, KGF, and sex steroids drive thymic senescence.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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