Comprehensive Transcriptomic Analysis for Thymic Epithelial Cells of Aged Mice and Humans
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Thymic epithelial cells (TECs) play a critical role in thymic development and thymopoiesis. As individuals age, TECs undergo various changes that impact their functions, leading to a reduction in cell numbers and impaired thymic selection. These age-related alterations have been observed in both mice and humans. However, the precise mechanisms underlying age-related TEC dysfunction remain unclear. Furthermore, there is a lack of a comprehensive study that connects mouse and human biological processes in this area. To address this gap, we conducted an extensive transcriptome analysis of young and old TECs in mice, complemented by further analysis of publicly available human TEC single-cell RNA sequencing data. Our analysis revealed alterations in both known and unknown pathways that potentially contribute to age-related TEC dysfunction. Specifically, we observed downregulation of pathways related to cell proliferation, T cell development, metabolism, and cytokine signaling in old age TECs. Conversely, TGF-β, BMP, and Wnt signaling pathways were upregulated, which have been known to be associated with age-related TEC dysfunctions or newly discovered in this study. Importantly, we found that these age-related changes in mouse TECs were consistently present in human TECs as well. This cross-species validation further strengthens the significance of our findings. In conclusion, our comprehensive analysis provides valuable insight into the biological and immunological characteristics of aged TECs in both mice and humans. These findings contribute to a better understanding of thymic involution and age-induced immune dysfunction.
Abstract
Thymic epithelial cells (TECs) play a critical role in thymic development and thymopoiesis. As individuals age, TECs undergo various changes that impact their functions, leading to a reduction in cell numbers and impaired thymic selection. These age-related alterations have been observed in both mice and humans. However, the precise mechanisms underlying age-related TEC dysfunction remain unclear. Furthermore, there is a lack of a comprehensive study that connects mouse and human biological processes in this area. To address this gap, we conducted an extensive transcriptome analysis of young and old TECs in mice, complemented by further analysis of publicly available human TEC single-cell RNA sequencing data. Our analysis revealed alterations in both known and unknown pathways that potentially contribute to age-related TEC dysfunction. Specifically, we observed downregulation of pathways related to cell proliferation, T cell development, metabolism, and cytokine signaling in old age TECs. Conversely, TGF-β, BMP, and Wnt signaling pathways were upregulated, which have been known to be associated with age-related TEC dysfunctions or newly discovered in this study. Importantly, we found that these age-related changes in mouse TECs were consistently present in human TECs as well. This cross-species validation further strengthens the significance of our findings. In conclusion, our comprehensive analysis provides valuable insight into the biological and immunological characteristics of aged TECs in both mice and humans. These findings contribute to a better understanding of thymic involution and age-induced immune dysfunction.
참고문헌 (54)
- Wang HX, "Thymic epithelial cells contribute to thymopoiesis and T cell development", Front Immunol, 10, pp.3099~ (2020)
- Abramson J, "Thymic epithelial cells", Annu Rev Immunol, 35, pp.85~118 (2017)
- Shanley DP, "An evolutionary perspective on the mechanisms of immunosenescence", Trends Immunol, 30, pp.374~381 (2009)
- Liang Z, "Age-related thymic involution : mechanisms and functional impact", Aging Cell, 21, pp.e13671~ (2022)
- Gui J, "Thymus size and age-related thymic involution : early programming, sexual dimorphism, progenitors and stroma", Aging Dis, 3, pp.280~290 (2012)
- Palmer S, "Thymic involution and rising disease incidence with age", Proc Natl Acad Sci U S A, 115, pp.1883~1888 (2018)
- Palmer DB, "The effect of age on thymic function", Front Immunol, 4, pp.316~ (2013)
- Goronzy JJ, "Aging, autoimmunity and arthritis : T-cell senescence and contraction of T-cell repertoire diversity-catalysts of autoimmunity and chronic inflammation", Arthritis Res Ther, 5, pp.225~234 (2003)
- Dumont-Lagacé M, "Sex hormones have pervasive effects on thymic epithelial cells", Sci Rep, 5, pp.12895~ (2015)
- Swann JB, "Elevated levels of Wnt signaling disrupt thymus morphogenesis and function", Sci Rep, 7, pp.785~ (2017)
- Hauri-Hohl MM, "TGF-beta signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution", Blood, 112, pp.626~634 (2008)
- Romano R, "Foxn1 : a master regulator gene of thymic epithelial development program", Front Immunol, 4, pp.187~ (2013)
- Baran-Gale J, "Ageing compromises mouse thymus function and remodels epithelial cell differentiation", Elife, 9, pp.e56221~ (2020)
- Tong QY, "Human thymic involution and aging in humanized mice", Front Immunol, 11, pp.1399~ (2020)
- Fujimori S, "Fine-tuning of β-catenin in mouse thymic epithelial cells is required for postnatal T-cell development", Elife, 11, pp.e69088~ (2022)
- Dutilh BE, "Decline in excision circles requires homeostatic renewal or homeostatic death of naive T cells", J Theor Biol, 224, pp.351~358 (2003)
- den Braber I, "Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans", Immunity, 36, pp.288~297 (2012)
- Bautista JL, "Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla", Nat Commun, 12, pp.1096~ (2021)
- Dobin A, "STAR : ultrafast universal RNA-seq aligner", Bioinformatics, 29, pp.15~21 (2013)
- Li B, "RSEM : accurate transcript quantification from RNA-seq data with or without a reference genome", BMC Bioinformatics, 12, pp.323~ (2011)
- Sun J, "TCC : an R package for comparing tag count data with robust normalization strategies", BMC Bioinformatics, 14, pp.219~ (2013)
- Love MI, "Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2", Genome Biol, 15, pp.550~ (2014)
- Robinson MD, "edgeR : a Bioconductor package for differential expression analysis of digital gene expression data", Bioinformatics, 26, pp.139~140 (2010)
- Subramanian A, "Gene set enrichment analysis : a knowledge-based approach for interpreting genome-wide expression profiles", Proc Natl Acad Sci U S A, 102, pp.15545~15550 (2005)
- Szklarczyk D, "The STRING database in 2023 : protein-protein association networks and functional enrichment analyses for any sequenced genome of interest", Nucleic Acids Res, 51, pp.D638~D646 (2023)
- Qi Y, "Aire and Fezf2, two regulators in medullary thymic epithelial cells, control autoimmune diseases by regulating TSAs : partner or complementer?", Front Immunol, 13, pp.948259~ (2022)
- Takaba H, "Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance", Cell, 163, pp.975~987 (2015)
- Shitara S, "IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRγδ+ intraepithelial lymphocytes", J Immunol, 190, pp.6173~6179 (2013)
- Tao H, "Thymic epithelial cell-derived IL-15 and IL-15 receptor α chain foster local environment for type 1 innate like T cell development", Front Immunol, 12, pp.623280~ (2021)
- Cowan JE, "Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth", Nat Commun, 10, pp.5498~ (2019)
- Rodrigues PM, "Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice", Blood, 130, pp.478~488 (2017)
- Shen H, "Medullary thymic epithelial NF-kB-inducing kinase(NIK)", IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice, 2019, pp.116, 19090~19097
- Park JE, "A cell atlas of human thymic development defines T cell repertoire formation", Science, 367 (2020)
- Liu Y, "Zeb1 links epithelial-mesenchymal transition and cellular senescence", Development, 135, pp.579~588 (2008)
- Zhu QQ, "The role of TWIST1 in epithelial-mesenchymal transition and cancers", Tumour Biol, 37, pp.185~197 (2016)
- Reichmann E, "Activation of an inducible c-FosER fusion protein causes loss of epithelial polarity and triggers epithelial-fibroblastoid cell conversion", Cell, 71, pp.1103~1116 (1992)
- Satoh R, "Requirement of stat3 signaling in the postnatal development of thymic medullary epithelial cells", PLoS Genet, 12, pp.e1005776~ (2016)
- Barthlott T, "Indispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2", Nat Commun, 12, pp.3933~ (2021)
- Kadouri N, "Transcriptional regulation of the thymus master regulator Foxn1", Sci Immunol, 7 (2022)
- Hu C, "Epigenetic modifications in thymic epithelial cells : an evolutionary perspective for thymus atrophy", Clin Epigenetics, 13, pp.210~ (2021)
- Castelo-Branco C, "The immune system and aging : a review", Gynecol Endocrinol, 30, pp.16~22 (2014)
- Thomas R, "Contributions of age-related thymic involution to immunosenescence and inflammaging", Immun Ageing, 17, pp.2~ (2020)
- Elyahu Y, "Thymus involution sets the clock of the aging T-cell landscape : implications for declined immunity and tissue repair", Ageing Res Rev, 65, pp.101231~ (2021)
- Boehm T, "Thymus involution and regeneration : two sides of the same coin?", Nat Rev Immunol, 13, pp.831~838 (2013)
- Semwal MK, "Metabolic regulation of thymic epithelial cell function", Front Immunol, 12, pp.636072~ (2021)
- Griffith AV, "Metabolic damage and premature thymus aging caused by stromal catalase deficiency", Cell Reports, 12, pp.1071~1079 (2015)
- Balciunaite G, "Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice", Nat Immunol, 3, pp.1102~1108 (2002)
- Bleul CC, "BMP signaling is required for normal thymus development", J Immunol, 175, pp.5213~5221 (2005)
- Frey P, "Canonical bmp signaling executes epithelial-mesenchymal transition downstream of snail1", Cancers(Basel), 12, pp.1019~ (2020)
- Gordon J, "Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis", Dev Biol, 339, pp.141~154 (2010)
- Swann JB, "Cooperative interaction of BMP signalling and Foxn1 gene dosage determines the size of the functionally active thymic epithelial compartment", Sci Rep, 7, pp.8492~ (2017)
- Wertheimer T, "Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration", Sci Immunol, 3 (2018)
- Yu FX, "Hippo pathway in organ size control, tissue homeostasis, and cancer", Cell, 163, pp.811~828 (2015)
- Ucar O, "A thymic epithelial stem cell pool persists throughout ontogeny and is modulated by TGF-β", Cell Reports, 17, pp.448~457 (2016)