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1.
Stem Cell Rev Rep ; 20(5): 1325-1339, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38519702

RESUMO

BACKGROUND: Similar to induced pluripotent cells (iPSCs), induced neural stem cells (iNSCs) can be directly converted from human somatic cells such as dermal fibroblasts and peripheral blood monocytes. While previous studies have demonstrated the resemblance of iNSCs to neural stem cells derived from primary sources and embryonic stem cells, respectively, a comprehensive analysis of the correlation between iNSCs and their physiological counterparts remained to be investigated. METHODS: Nowadays, single-cell sequencing technologies provide unique opportunities for in-depth cellular benchmarking of complex cell populations. Our study involves the comprehensive profiling of converted human iNSCs at a single-cell transcriptomic level, alongside conventional methods, like flow cytometry and immunofluorescence stainings. RESULTS: Our results show that the iNSC conversion yields a homogeneous cell population expressing bona fide neural stem cell markers. Extracting transcriptomic signatures from published single cell transcriptomic atlas data and comparison to the iNSC transcriptome reveals resemblance to embryonic neuroepithelial cells of early neurodevelopmental stages observed in vivo at 5 weeks of development. CONCLUSION: Our data underscore the physiological relevance of directly converted iNSCs, making them a valuable in vitro system for modeling human central nervous system development and establishing translational applications in cell therapy and compound screening.


Assuntos
Sistema Nervoso Central , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Análise de Célula Única , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Transcriptoma/genética , Diferenciação Celular/genética , Reprogramação Celular , Perfilação da Expressão Gênica , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo
2.
Stem Cell Res ; 61: 102784, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35453044

RESUMO

Congenital hyperinsulinemic hypoglycemia (HH) is the most frequent cause of persistent and recurrent hypoglycemia. Peripheral mononuclear blood cells (PBMCs) from a patient diagnosed with HH, alongside autism-spectrum-disorder (ASD), carrying a heterozygous c.812 T>A (L271H) mutation in the voltage-gated calcium channel subunit Cav1.3-encoding gene CACNA1D, were reprogrammed into induced pluripotent stem cells (iPSC). The CACNA1D L271H iPSC (IBKMOLi002-A) exhibit a normal karyotype, high expression of pluripotency-associated markers and the capacity to differentiate into cells of all three germ layers. We provide a novel patient-specific iPSC line, allowing to study HH, ASD, the associated neurodevelopmental disorder as well as CACNA1D-associated channelopathies in general.


Assuntos
Hipoglicemia , Células-Tronco Pluripotentes Induzidas , Células Sanguíneas , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Humanos , Hipoglicemia/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética
3.
Front Immunol ; 10: 472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936873

RESUMO

Activation of the immune system increases systemic adrenal-derived glucocorticoid (GC) levels which downregulate the immune response as part of a negative feedback loop. While CD4+ T cells are essential target cells affected by GC, it is not known whether these hormones exert their major effects on CD4+ helper T cells, CD4+Foxp3+ regulatory T cells (Treg cells), or both. Here, we generated mice with a specific deletion of the glucocorticoid receptor (GR) in Foxp3+ Treg cells. Remarkably, while basal Treg cell characteristics and in vitro suppression capacity were unchanged, Treg cells lacking the GR did not prevent the induction of inflammatory bowel disease in an in vivo mouse model. Under inflammatory conditions, GR-deficient Treg cells acquired Th1-like characteristics and expressed IFN-gamma, but not IL-17, and failed to inhibit pro-inflammatory CD4+ T cell expansion in situ. These findings reveal that the GR is critical for Foxp3+ Treg cell function and suggest that endogenous GC prevent Treg cell plasticity toward a Th1-like Treg cell phenotype in experimental colitis. When equally active in humans, a rationale is provided to develop GC-mimicking therapeutic strategies which specifically target Foxp3+ Treg cells for the treatment of inflammatory bowel disease.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Receptores de Glucocorticoides/fisiologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva/efeitos adversos , Animais , Anticorpos Antinucleares/biossíntese , Linfócitos T CD4-Positivos/imunologia , Sobrevivência Celular , Colite/etiologia , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/análise , Técnicas de Silenciamento de Genes , Glucocorticoides/fisiologia , Ativação Linfocitária , Masculino , Camundongos , Especificidade de Órgãos , Receptores de Glucocorticoides/deficiência , Receptores de Glucocorticoides/genética , Tolerância a Antígenos Próprios , Baço/imunologia , Baço/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Linfócitos T Reguladores/química , Timo/imunologia , Timo/patologia
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