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Auteur Meng LI |
Documents disponibles écrits par cet auteur (2)
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Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder / Daniel C. DE LA FUENTE ; Meng LI in Molecular Autism, 14 (2023)
[article]
Titre : Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder Type de document : Texte imprimé et/ou numérique Auteurs : Daniel C. DE LA FUENTE, Auteur ; Meng LI, Auteur Article en page(s) : 8 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite the association of SETBP1 with neurodevelopmental disorders, little is known about its role in brain development. METHODS: Using CRISPR/Cas9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs) and examined the effects of SETBP1-deficiency in neural progenitors (NPCs) and neurons derived from these stem cells using a battery of cellular assays, genome-wide transcriptomic profiling and drug-based phenotypic rescue. RESULTS: Neural induction occurred efficiently in all SETBP1 deletion models as indicated by uniform transition into neural rosettes. However, SETBP1-deficient NPCs exhibited an extended proliferative window and a decrease in neurogenesis coupled with a deficiency in their ability to acquire ventral forebrain fate. Genome-wide transcriptome profiling and protein biochemical analysis revealed enhanced activation of Wnt/?-catenin signaling in SETBP1 deleted cells. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule Wnt inhibitor XAV939 restored hyper canonical ?-catenin activity and restored both cortical and MGE neuronal differentiation. LIMITATIONS: The current study is based on analysis of isogenic hESC lines with genome-edited SETBP1 deletion and further studies would benefit from the use of patient-derived iPSC lines that may harbor additional genetic risk that aggravate brain pathology of SETBP1 disorder. CONCLUSIONS: We identified an important role for SETBP1 in controlling forebrain progenitor expansion and neurogenic differentiation. Our study establishes a novel regulatory link between SETBP1 and Wnt/?-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder. En ligne : http://dx.doi.org/10.1186/s13229-023-00540-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513
in Molecular Autism > 14 (2023) . - 8 p.[article] Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder [Texte imprimé et/ou numérique] / Daniel C. DE LA FUENTE, Auteur ; Meng LI, Auteur . - 8 p.
Langues : Anglais (eng)
in Molecular Autism > 14 (2023) . - 8 p.
Index. décimale : PER Périodiques Résumé : BACKGROUND: Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite the association of SETBP1 with neurodevelopmental disorders, little is known about its role in brain development. METHODS: Using CRISPR/Cas9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs) and examined the effects of SETBP1-deficiency in neural progenitors (NPCs) and neurons derived from these stem cells using a battery of cellular assays, genome-wide transcriptomic profiling and drug-based phenotypic rescue. RESULTS: Neural induction occurred efficiently in all SETBP1 deletion models as indicated by uniform transition into neural rosettes. However, SETBP1-deficient NPCs exhibited an extended proliferative window and a decrease in neurogenesis coupled with a deficiency in their ability to acquire ventral forebrain fate. Genome-wide transcriptome profiling and protein biochemical analysis revealed enhanced activation of Wnt/?-catenin signaling in SETBP1 deleted cells. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule Wnt inhibitor XAV939 restored hyper canonical ?-catenin activity and restored both cortical and MGE neuronal differentiation. LIMITATIONS: The current study is based on analysis of isogenic hESC lines with genome-edited SETBP1 deletion and further studies would benefit from the use of patient-derived iPSC lines that may harbor additional genetic risk that aggravate brain pathology of SETBP1 disorder. CONCLUSIONS: We identified an important role for SETBP1 in controlling forebrain progenitor expansion and neurogenic differentiation. Our study establishes a novel regulatory link between SETBP1 and Wnt/?-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder. En ligne : http://dx.doi.org/10.1186/s13229-023-00540-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513 TH1/Treg ratio may be a marker of autism in children with immune dysfunction / Zu-Qing NIE in Research in Autism Spectrum Disorders, 101 (March 2023)
[article]
Titre : TH1/Treg ratio may be a marker of autism in children with immune dysfunction Type de document : Texte imprimé et/ou numérique Auteurs : Zu-Qing NIE, Auteur ; Dong HAN, Auteur ; Kun ZHANG, Auteur ; Meng LI, Auteur ; Ho-Keun KWON, Auteur ; Sin-Hyeog IM, Auteur ; Li XU, Auteur ; Ji-chun YANG, Auteur ; Zhi-Wei LI, Auteur ; Xin-Wei HUANG, Auteur ; Jie WEN, Auteur ; Yang SHU-JUN, Auteur ; Fang YIN, Auteur ; Chen SHEN, Auteur ; Paul ASHWOOD, Auteur ; Chuan-Yuan KANG, Auteur ; Xia CAO, Auteur Article en page(s) : 102085 Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD) T cells Regulation Cytokines T helper T helper-1 T regulatory cell Neurodevelopment Immune Index. décimale : PER Périodiques Résumé : Evidence suggests a link between autism spectrum disorder (ASD), behavioral symptoms in the context of ASD, and presence of an altered immune function. Several studies have highlighted differences in T-lymphocyte subpopulations, their activation status, and their response to stimulation in children and adults with ASD. These T cell abnormalities have often been associated with more impaired behaviors. However, few studies have attempted to address whether T cell subsets have the potential to serve as biomarkers in ASD. Moreover, although many studies have been performed in Western populations, few (if any) have been performed in Asian populations in mainland China. In this study we used intracellular cytokine flow cytometry to assess the frequencies of CD4+ T-cell subpopulations (T-helper (TH) 1, TH2, TH17, Foxp3+ regulatory T cells (Treg) as well as CD8+, subpopulations of T cytotoxic (TC) 1, TC2, and TC17 in 82 children with ASD and 50 healthy typical developing children from the Second Affiliated Hospital of Kunming Medical University of Yunnan province. To further elucidate immune status cytokine levels were also measured in the plasma and serum using a bead-based cytokine assay. Our results showed that the frequency of circulating Treg cells and the levels of active TGF-Î21 in plasma were lower in children with ASD than in healthy controls. In contrast, the frequencies of TH1, TH2, TH17 and TC1 cells were increased. Proinflammatory cytokine levels of TNF-Î+, IL-4, IL-5 and IL-17A were higher in the plasma of children with ASD compared to typical controls. We also found an association between the severity of behavior impairments in ASD children and altered immune responses as measured using the effector T cell responses and regulatory responses (using Teff/Treg ratios). Higher the Teff/Treg ratios, were associated with more severe problematic behavioral symptoms. Further, the potential biomarker relevance of Teff/Treg ratio was evaluated by the receiver operating characteristics curve. Data suggests that high TH1/Treg cell ratios could also be used as a potential marker for the diagnosis of children with ASD. Overall, our data suggest an imbalance in inflammatory and regulatory immune responses in ASD. Ratios of inflammatory/regulatory cells or cell frequencies such as Teff/Treg cells may be useful biomarkers for children with ASD with immune dysfunction. En ligne : https://doi.org/10.1016/j.rasd.2022.102085 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=492
in Research in Autism Spectrum Disorders > 101 (March 2023) . - 102085[article] TH1/Treg ratio may be a marker of autism in children with immune dysfunction [Texte imprimé et/ou numérique] / Zu-Qing NIE, Auteur ; Dong HAN, Auteur ; Kun ZHANG, Auteur ; Meng LI, Auteur ; Ho-Keun KWON, Auteur ; Sin-Hyeog IM, Auteur ; Li XU, Auteur ; Ji-chun YANG, Auteur ; Zhi-Wei LI, Auteur ; Xin-Wei HUANG, Auteur ; Jie WEN, Auteur ; Yang SHU-JUN, Auteur ; Fang YIN, Auteur ; Chen SHEN, Auteur ; Paul ASHWOOD, Auteur ; Chuan-Yuan KANG, Auteur ; Xia CAO, Auteur . - 102085.
Langues : Anglais (eng)
in Research in Autism Spectrum Disorders > 101 (March 2023) . - 102085
Mots-clés : Autism spectrum disorder (ASD) T cells Regulation Cytokines T helper T helper-1 T regulatory cell Neurodevelopment Immune Index. décimale : PER Périodiques Résumé : Evidence suggests a link between autism spectrum disorder (ASD), behavioral symptoms in the context of ASD, and presence of an altered immune function. Several studies have highlighted differences in T-lymphocyte subpopulations, their activation status, and their response to stimulation in children and adults with ASD. These T cell abnormalities have often been associated with more impaired behaviors. However, few studies have attempted to address whether T cell subsets have the potential to serve as biomarkers in ASD. Moreover, although many studies have been performed in Western populations, few (if any) have been performed in Asian populations in mainland China. In this study we used intracellular cytokine flow cytometry to assess the frequencies of CD4+ T-cell subpopulations (T-helper (TH) 1, TH2, TH17, Foxp3+ regulatory T cells (Treg) as well as CD8+, subpopulations of T cytotoxic (TC) 1, TC2, and TC17 in 82 children with ASD and 50 healthy typical developing children from the Second Affiliated Hospital of Kunming Medical University of Yunnan province. To further elucidate immune status cytokine levels were also measured in the plasma and serum using a bead-based cytokine assay. Our results showed that the frequency of circulating Treg cells and the levels of active TGF-Î21 in plasma were lower in children with ASD than in healthy controls. In contrast, the frequencies of TH1, TH2, TH17 and TC1 cells were increased. Proinflammatory cytokine levels of TNF-Î+, IL-4, IL-5 and IL-17A were higher in the plasma of children with ASD compared to typical controls. We also found an association between the severity of behavior impairments in ASD children and altered immune responses as measured using the effector T cell responses and regulatory responses (using Teff/Treg ratios). Higher the Teff/Treg ratios, were associated with more severe problematic behavioral symptoms. Further, the potential biomarker relevance of Teff/Treg ratio was evaluated by the receiver operating characteristics curve. Data suggests that high TH1/Treg cell ratios could also be used as a potential marker for the diagnosis of children with ASD. Overall, our data suggest an imbalance in inflammatory and regulatory immune responses in ASD. Ratios of inflammatory/regulatory cells or cell frequencies such as Teff/Treg cells may be useful biomarkers for children with ASD with immune dysfunction. En ligne : https://doi.org/10.1016/j.rasd.2022.102085 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=492