Dysregulated calcium underlies hyposalivation and microbial dysbiosis in Down syndrome
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE331212 | GEO | 2026/05/29
REPOSITORIES: GEO
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Project description:Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). However, the mechanisms by which T21 causes susceptibility to CHDs are poorly understood. Here, using a combination of human induced pluripotent stem cell (iPSC)-based model and Dp(16)1Yey/+ (Dp16) a mouse model of DS, we identified downregulation of canonical Wnt signaling that is caused by increased dosage of interferon (IFN) receptors encoded on chromosome 21 (HSA21) as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS as well as CHDs (DS/CHD iPSCs), and controls (control iPSCs) into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN pathways restored canonical WNT signaling and rescued defects during cardiac differentiation of DS/CHD iPSCs. Strikingly, treatment with an inhibitor of Janus kinase, which is activated by IFN receptor engagement normalized the canonical Wnt pathway and ameliorated CHDs in Dp16 embryos. Our findings provide new mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.
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Project description:Primary Sjogren’s syndrome (pSS) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been considered a driver in pSS development. Saliva production is regulated by sympathetic input into the gland initiating intracellular Ca2+ signals that activate the store operated Ca2+ entry (SOCE) pathway eliciting sustained Ca2+ influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models or its impact on pSS. Here we report that male and female mice lacking Stim1 and Stim2 (Stim1/2K14Cre) in salivary glands hyposalivate upon pilocarpine stimulation and showed reduced intracellular Ca2+ levels via SOCE in parotid acini. Bulk RNASeq of the parotid glands of Stim1/2K14Cre showed a decrease in Stim1/2 genes but not in other Ca2+ associated genes mediating saliva fluid secretion, yet SOCE was functionally required for the activation of the Ca2+ activated chloride channel ANO1. Ageing Stim1/2K14Cre mice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum which may be linked to the downregulation of the toll-like receptor 8 (Tlr8) in Stim1/2K14Cre mice. This is supported by an increase in TLR8 gene expression in a salivary gland cell line following SOCE stimulation. Moreover, salivary gland biopsies of pSS patients showed increased STIM1 and TLR8 expression. These results implicate SOCE as an important activator of ANO1 and saliva fluid secretion in salivary glands but loss of SOCE does not result in pSS. Importantly, our data suggest a link between SOCE and TLR8 signaling which may have implications in inflammatory responses in salivary glands.
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Project description:Down syndrome (DS), the most common human chromosomal disorder, is caused by trisomy 21. Recent studies show that the trisomic genes Dyrk1a and Kcnj6 play critical causative roles in DS cognitive deficits. Interestingly, an unexpected lack of improvement of hippocampal-dependent learning and memory deficits was observed when both Dyrk1a and Kcnj6 were normalized to diploidy in the DS mouse model, Dp(16)1/Yey (Dp16). In this study, we explored the molecular mechanisms underlying this phenomenon by using whole genome-wide hippocampal transcriptome analysis. In total, 142, 142, and 112 genes were found significantly differentially expressed in the Dp16, Dp16/Dyrk1aKO (Dyrk1a normalized) and Dp16;Dyrk1aKO/Kcnj6KO (Both Dyrk1a and Kcnj6 normalized) hippocampus, respectively, compared with the WT hippocampus. The majority of the common significantly differentially expressed genes (DEGs) were trisomic genes. Dyrk1a and Kcnj6 normalization mainly altered the expression of diploid genes. Normalizing Dyrk1a in the Dp16 hippocampus caused an overall downregulation of genes, whereas further Kcnj6 normalization caused an overall upregulation of genes. Both further rescuing effects and neutralizing effects were observed in Kcnj6 and Dyrk1a double-normalized mice compared with mice with Dyrk1a normalization alone.
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Project description:Down syndrome (DS), a genetic condition leading to intellectual disability, is characterized by triplication of human chromosome 21. Neuropathological hallmarks of DS include abnormal central nervous system development that manifests during gestation and extends throughout life. As a result, newborns and adults with DS exhibit cognitive and motor deficits and fail to meet typical developmental and lack independent life skills. A critical outstanding question is how DS-specific prenatal and postnatal phenotypes are recapitulated in different mouse models. To begin answering this question, we developed a life span approach to directly compare differences in embryonic brain development, cellularity, gene expression, neonatal and adult behavior behavior in three cytogenetically distinct mouse models of DS—Ts1Cje, Ts65Dn and Dp16/1Yey (Dp16). In the last two decades multiple therapeutic trials have been attempted to improve cognition in humans with DS but the results of these interventions lacked efficacy despide their succes in the Ts65Dn mouse model of DS. To better understand how phenotypic changes in humans in DS are recapitulated in different mouse models, we copared embryonic brain development and gene expression, perinatal behavior and brain excitatoty/inhibitory cell distribution, and adult behavior and gene expression in the Dp16, Ts65Dn and Ts1Cje mouse models of DS. The objectives of this study were to determine the best model(s) for prenatal and postnatal therapeutic trials and to identify treatment endpoints that can be used to evaluate the fficacy of these therapies prior to human clinical trials. Our data showed that, at embryonic day 15.5, Ts65Dn mice are the most profoundly and consistently affected with respect to somatic growth, brain morphogenesis, and neurogenesis compared to Ts1Cje and Dp16 embryos. However, gene expression results show that both Ts65Dn and Ts1Cje embryonic forebrains have a relatively high number of differentially expressed genes compared to Dp16, with little overlap in gene identities and genomic distribution observed among these models. Additionally, postnatal histological analyses show varying degrees of cell population and brain histogenesis abnormalities among the three strains. Behavioral testing also highlights differences among the models in their ability to meet various developmental milestones. At adulthood, Ts65Dn and Ts1Cje showed hyperactive behavior in the open field test but not Dp16 mice. In the fear conditioning test, all three strains showed lower freezing versus eupploid mice; Dp16 were the most severely affected. In the Morris water maze, Ts65Dn showed significant delays in the hidden platform, probe and reversal trials. Dp16 mice showed milder deficits in the hidden platform trial but severe deficits in reversal. Ts1Cje mice had no spatial memory deficits. In the rotarod test, Dp16 performed poorly in fixed and accelerating speed trials, while Ts1Cje was only abnormal at high speeds. Ts65Dn rotarod performance was unaffected. Compared to euploid, Ts65Dn had a higher number of differentially expressed (DEX) genes in cortex and cerebellum, while Ts1Cje had more DEX genes in hippocampus and cerebellum. Dp16 had the lowest number of DEX genes in all regions analyzed. Pathway analyses highlighted commonly dysregulated pathways, including G-protein signaling, oxidative stress, interferon signaling, glycosylation and disulfide bonds.
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Project description:Over the last years, proteomic techniques have been demonstrated to be valuable tools for analysing the periodontal proteome in saliva samples, contributing to identifying extensive and comprehensive protein profiles associated with periodontitis. However, the periodontal proteome has not yet been studied using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Consequently, the objective of the present longitudinal research was to study the periodontal proteome in saliva in three clinical conditions (periodontal health, untreated periodontitis, and treated periodontitis), applying SWATH-MS to 1) analyse the periodontal proteome structure in the three clinical groups, 2) compare the differential protein expression between the three clinical groups, and 3) evaluate the diagnostic accuracy of the proteins quantified to identify new biomarkers with a high capacity to discriminate the three clinical conditions. A total of 85 subjects, 44 periodontally healthy and 41 with generalised untreated periodontitis in stages III-IV, were included, and saliva samples were collected. The diagnosis of periodontal status was conducted by two experienced dentists using clinical and radiographic criteria. The definition of periodontal status was established following the Classification of Periodontal Diseases and Conditions published in 2018. In the untreated periodontitis group, 38 underwent conventional non-surgical treatment and were evaluated clinically after two months (treated periodontitis group). In the revaluation, 36 individuals showed significant clinical improvement in the mean full-mouth probing pocket depth (PPD) value, and saliva samples were collected from them.
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Project description:Human salispheres, a culture of stem/progenitor cells, represent a potential therapy for radiation induced hyposalivation. Radiation-induced hyposalivation dramatically reduces quality of life of patients. We have demonstrated the potential of human salispheres to engraft and differentiate when transplanted into a mouse model of hyposalivation, in the manuscript associated with these data. We also demonstrate the functional recovery of irradiated salivary glands (SGs) following human salisphere transplantation, by the measurement of saliva production. We previously employed Illumina microarrays to determine if transplanted human salisphere cells exert a paracrine stimulatory effect on recipient mouse SGs. Results of this array unveiled a large cohort of immuneresponse genes unregulated following human salisphere transplantation. In order to negate this immune response and unveil any true paracrein stimulatory effects, we performed autologous transplantation of salispheres from NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, the same model employed in our first microarray study, in the irradiated SGs of NSG mice. 6 samples were analysed in total. Total RNA from 3 irradiated control SGs (5Gy irradiation) and 3 salivary glands transplanted with 100,000 NSG salispheres.
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Project description:Human salispheres, a culture of stem/progenitor cells, represent a potential therapy for radiation induced hyposalivation. Radiation-induced hyposalivation dramatically reduces quality of life of patients. We have demonstrated the potential of human salispheres to engraft and differentiate when transplanted into a mouse model of hyposalivation, in the manuscript associated with these data. We also demonstrate the functional recovery of irradiated salivary glands (SGs) following human salisphere transplantation, by the measurement of saliva production. We previously employed Illumina microarrays to determine if transplanted human salisphere cells exert a paracrine stimulatory effect on recipient mouse SGs. Results of this array unveiled a large cohort of immuneresponse genes unregulated following human salisphere transplantation. In order to negate this immune response and unveil any true paracrein stimulatory effects, we performed autologous transplantation of salispheres from NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, the same model employed in our first microarray study, in the irradiated SGs of NSG mice.
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Project description:Human salispheres, a culture of stem/progenitor cells, represent a potential therapy for radiation induced hyposalivation. Radiation-induced hyposalivation dramatically reduces quality of life of patients. We have demonstrated the potential of human salispheres to engraft and differentiate when transplanted into a mouse model of hyposalivation, in the manuscript associated with these data. We also demonstrate the functional recovery of irradiated salivary glands (SGs) following human salisphere transplantation, by the measurement of saliva production. When analyzing human salisphere- transplanted SGs for the presence of human cells, we noted that the highest proportion of human cells were present 1 week after transplantation. This microarray study was designed to determine if paracrine signaling from transplanted human salisphere cells to recipient mouse SGs accounts for a part of the functional recovery of the recipient SG we observe. We compare the transcriptome from irradiated control SG of immunecompromised NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice with that of NSG SGs transplanted with 100,000 human salisphere cells. All mice were sacrificed 1 week following transplantation (or non-transplantation in case of controls) and Illumina array chips used to detect differences in gene expression. 6 samples were analysed in total. Total RNA from 3 irradiated control SGs (5Gy irradiation) and 3 salivary glands transplanted with 100,000 human salispheres.
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