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1.
J Neuroophthalmol ; 44(3): 419-422, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38578695

RESUMO

BACKGROUND: Ocular myasthenia gravis is treated predominantly by oral medications, with the potential for systemic adverse effects. Successful treatment has been achieved using peribulbar dexamethasone. We assessed the effect of peribulbar dexamethasone or triamcinolone (40-mg Triesence), a longer-acting corticosteroid, targeting the peribulbar area as opposed to directly injecting the affected extraocular muscle. This more convenient and secure approach holds the potential for straightforward integration within clinical environments. METHODS: Retrospective chart review. RESULTS: Five patients were identified that were treated with peribulbar corticosteroids. In 4 of the 5 cases, ophthalmoparesis was unilateral. One case had isolated ptosis, and 4 had both ptosis and ophthalmoparesis. Three of these 4 cases reported complete resolution of symptoms within weeks of a single injection. Improvement lasted between 5 to 6 months, and all patients responded to repeated injections. CONCLUSIONS: Peribulbar corticosteroids can be effective in ocular myasthenia gravis. We suggest that longer-acting agents such as triamcinolone are preferable, to reduce injection frequency.


Assuntos
Miastenia Gravis , Humanos , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/diagnóstico , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Glucocorticoides/uso terapêutico , Triancinolona/uso terapêutico , Triancinolona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Resultado do Tratamento , Músculos Oculomotores/efeitos dos fármacos , Músculos Oculomotores/fisiopatologia
2.
Stem Cell Reports ; 18(11): 2174-2189, 2023 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-37832543

RESUMO

A complete knockout of a single key pluripotency gene may drastically affect embryonic stem cell function and epigenetic reprogramming. In contrast, elimination of only one allele of a single pluripotency gene is mostly considered harmless to the cell. To understand whether complex haploinsufficiency exists in pluripotent cells, we simultaneously eliminated a single allele in different combinations of two pluripotency genes (i.e., Nanog+/-;Sall4+/-, Nanog+/-;Utf1+/-, Nanog+/-;Esrrb+/- and Sox2+/-;Sall4+/-). Although these double heterozygous mutant lines similarly contribute to chimeras, fibroblasts derived from these systems show a significant decrease in their ability to induce pluripotency. Tracing the stochastic expression of Sall4 and Nanog at early phases of reprogramming could not explain the seen delay or blockage. Further exploration identifies abnormal methylation around pluripotent and developmental genes in the double heterozygous mutant fibroblasts, which could be rescued by hypomethylating agent or high OSKM levels. This study emphasizes the importance of maintaining two intact alleles for pluripotency induction.


Assuntos
Metilação de DNA , Células-Tronco Pluripotentes Induzidas , Metilação de DNA/genética , Reprogramação Celular/genética , Haploinsuficiência , Fibroblastos/metabolismo , Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo
3.
Nat Commun ; 14(1): 3359, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37291192

RESUMO

Human trophoblast stem cells (hTSCs) can be derived from embryonic stem cells (hESCs) or be induced from somatic cells by OCT4, SOX2, KLF4 and MYC (OSKM). Here we explore whether the hTSC state can be induced independently of pluripotency, and what are the mechanisms underlying its acquisition. We identify GATA3, OCT4, KLF4 and MYC (GOKM) as a combination of factors that can generate functional hiTSCs from fibroblasts. Transcriptomic analysis of stable GOKM- and OSKM-hiTSCs reveals 94 hTSC-specific genes that are aberrant specifically in OSKM-derived hiTSCs. Through time-course-RNA-seq analysis, H3K4me2 deposition and chromatin accessibility, we demonstrate that GOKM exert greater chromatin opening activity than OSKM. While GOKM primarily target hTSC-specific loci, OSKM mainly induce the hTSC state via targeting hESC and hTSC shared loci. Finally, we show that GOKM efficiently generate hiTSCs from fibroblasts that harbor knockout for pluripotency genes, further emphasizing that pluripotency is dispensable for hTSC state acquisition.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas , Humanos , Reprogramação Celular/genética , Trofoblastos , Fibroblastos , Células-Tronco Embrionárias , Cromatina/genética , Fator 3 de Transcrição de Octâmero/genética
4.
J Mol Biol ; 432(8): 2754-2798, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32044344

RESUMO

Autophagy is an intracellular degradation process that is essential for cellular survival, tissue homeostasis, and human health. The housekeeping functions of autophagy in mediating the clearance of aggregation-prone proteins and damaged organelles are vital for post-mitotic neurons. Improper functioning of this process contributes to the pathology of myriad human diseases, including neurodegeneration. Impairment in autophagy has been reported in several neurodegenerative diseases where pharmacological induction of autophagy has therapeutic benefits in cellular and transgenic animal models. However, emerging studies suggest that the efficacy of autophagy inducers, as well as the nature of the autophagy defects, may be context-dependent, and therefore, studies in disease-relevant experimental systems may provide more insights for clinical translation to patients. With the advancements in human stem cell technology, it is now possible to establish disease-affected cellular platforms from patients for investigating disease mechanisms and identifying candidate drugs in the appropriate cell types, such as neurons that are otherwise not accessible. Towards this, patient-derived human induced pluripotent stem cells (hiPSCs) have demonstrated considerable promise in constituting a platform for effective disease modeling and drug discovery. Multiple studies have utilized hiPSC models of neurodegenerative diseases to study autophagy and evaluate the therapeutic efficacy of autophagy inducers in neuronal cells. This review provides an overview of the regulation of autophagy, generation of hiPSCs via cellular reprogramming, and neuronal differentiation. It outlines the findings in various neurodegenerative disorders where autophagy has been studied using hiPSC models.


Assuntos
Autofagia , Diferenciação Celular , Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Animais , Humanos
5.
Cell Stem Cell ; 24(6): 983-994.e7, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31031139

RESUMO

Following fertilization, totipotent cells undergo asymmetric cell divisions, resulting in three distinct cell types in the late pre-implantation blastocyst: epiblast (Epi), primitive endoderm (PrE), and trophectoderm (TE). Here, we aim to understand whether these three cell types can be induced from fibroblasts by one combination of transcription factors. By utilizing a sophisticated fluorescent knockin reporter system, we identified a combination of five transcription factors, Gata3, Eomes, Tfap2c, Myc, and Esrrb, that can reprogram fibroblasts into induced pluripotent stem cells (iPSCs), induced trophoblast stem cells (iTSCs), and induced extraembryonic endoderm stem cells (iXENs), concomitantly. In-depth transcriptomic, chromatin, and epigenetic analyses provide insights into the molecular mechanisms that underlie the reprogramming process toward the three cell types. Mechanistically, we show that the interplay between Esrrb and Eomes during the reprogramming process determines cell fate, where high levels of Esrrb induce a XEN-like state that drives pluripotency and high levels of Eomes drive trophectodermal fate.


Assuntos
Blastocisto/fisiologia , Endoderma/fisiologia , Fibroblastos/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Trofoblastos/fisiologia , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Reprogramação Celular , Implantação do Embrião , Camundongos , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo
6.
Cell Stem Cell ; 17(5): 543-56, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26412562

RESUMO

Induced pluripotent stem cells (iPSCs) undergo extensive nuclear reprogramming and are generally indistinguishable from embryonic stem cells (ESCs) in their functional capacity and transcriptome and DNA methylation profiles. However, direct conversion of cells from one lineage to another often yields incompletely reprogrammed, functionally compromised cells, raising the question of whether pluripotency is required to achieve a high degree of nuclear reprogramming. Here, we show that transient expression of Gata3, Eomes, and Tfap2c in mouse fibroblasts induces stable, transgene-independent trophoblast stem-like cells (iTSCs). iTSCs possess transcriptional profiles highly similar to blastocyst-derived TSCs, with comparable methylation and H3K27ac patterns and genome-wide H2A.X deposition. iTSCs generate trophoectodermal lineages upon differentiation, form hemorrhagic lesions, and contribute to developing placentas in chimera assays, indicating a high degree of nuclear reprogramming, with no evidence of passage through a transient pluripotent state. Together, these data demonstrate that extensive nuclear reprogramming can be achieved independently of pluripotency.


Assuntos
Linhagem da Célula , Núcleo Celular/metabolismo , Reprogramação Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Trofoblastos/citologia , Animais , Células Cultivadas , Camundongos , Camundongos Transgênicos , Trofoblastos/metabolismo
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