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1.
Development ; 150(13)2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37376888

RESUMEN

The reactivation of developmental genes and pathways during adulthood may contribute to pathogenesis of diseases such as prostate cancer. Analysis of the mechanistic links between development and disease could be exploited to identify signalling pathways leading to disease in the prostate. However, the mechanisms underpinning prostate development require further characterisation to interrogate fully the link between development and disease. Previously, our group developed methods to produce prostate organoids using induced pluripotent stem cells (iPSCs). Here, we show that human iPSCs can be differentiated into prostate organoids using neonatal rat seminal vesicle mesenchyme in vitro. The organoids can be used to study prostate development or modified to study prostate cancer. We also elucidated molecular drivers of prostate induction through RNA-sequencing analyses of the rat urogenital sinus and neonatal seminal vesicles. We identified candidate drivers of prostate development evident in the inductive mesenchyme and epithelium involved with prostate specification. Our top candidates included Spx, Trib3, Snai1, Snai2, Nrg2 and Lrp4. This work lays the foundations for further interrogation of the reactivation of developmental genes in adulthood, leading to prostate disease.


Asunto(s)
Células Madre Pluripotentes Inducidas , Neoplasias de la Próstata , Masculino , Humanos , Ratas , Animales , Próstata , Roedores , Sistema Urogenital/fisiología , Diferenciación Celular/genética , Organoides
2.
Glia ; 71(2): 168-186, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36373840

RESUMEN

Extensive microglia reactivity has been well described in human and experimental temporal lobe epilepsy (TLE). To date, however, it is not clear whether and based on which molecular mechanisms microglia contribute to the development and progression of focal epilepsy. Astroglial gap junction coupled networks play an important role in regulating neuronal activity and loss of interastrocytic coupling causally contributes to TLE. Here, we show in the unilateral intracortical kainate (KA) mouse model of TLE that reactive microglia are primary producers of tumor necrosis factor (TNF)α and contribute to astrocyte dysfunction and severity of status epilepticus (SE). Immunohistochemical analyses revealed pronounced and persistent microglia reactivity, which already started 4 h after KA-induced SE. Partial depletion of microglia using a colony stimulating factor 1 receptor inhibitor prevented early astrocyte uncoupling and attenuated the severity of SE, but increased the mortality of epileptic mice following surgery. Using microglia-specific inducible TNFα knockout mice we identified microglia as the major source of TNFα during early epileptogenesis. Importantly, microglia-specific TNFα knockout prevented SE-induced gap junction uncoupling in astrocytes. Continuous telemetric EEG recordings revealed that during the first 4 weeks after SE induction, microglial TNFα did not significantly contribute to spontaneous generalized seizure activity. Moreover, the absence of microglial TNFα did not affect the development of hippocampal sclerosis but attenuated gliosis. Taken together, these data implicate reactive microglia in astrocyte dysfunction and network hyperexcitability after an epileptogenic insult.


Asunto(s)
Epilepsia del Lóbulo Temporal , Estado Epiléptico , Ratones , Animales , Humanos , Epilepsia del Lóbulo Temporal/patología , Astrocitos/patología , Factor de Necrosis Tumoral alfa , Microglía/patología , Hipocampo/patología , Convulsiones/patología , Estado Epiléptico/patología , Ácido Kaínico/toxicidad , Modelos Animales de Enfermedad , Ratones Noqueados
3.
Int J Mol Sci ; 22(23)2021 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-34884905

RESUMEN

The prostate is vulnerable to two major age-associated diseases, cancer and benign enlargement, which account for significant morbidity and mortality for men across the globe. Prostate cancer is the most common cancer reported in men, with over 1.2 million new cases diagnosed and 350,000 deaths recorded annually worldwide. Benign prostatic hyperplasia (BPH), characterised by the continuous enlargement of the adult prostate, symptomatically afflicts around 50% of men worldwide. A better understanding of the biological processes underpinning these diseases is needed to generate new treatment approaches. Developmental studies of the prostate have shed some light on the processes essential for prostate organogenesis, with many of these up- or downregulated genes expressions also observed in prostate cancer and/or BPH progression. These insights into human disease have been inferred through comparative biological studies relying primarily on rodent models. However, directly observing mechanisms of human prostate development has been more challenging due to limitations in accessing human foetal material. Induced pluripotent stem cells (iPSCs) could provide a suitable alternative as they can mimic embryonic cells, and iPSC-derived prostate organoids present a significant opportunity to study early human prostate developmental processes. In this review, we discuss the current understanding of prostate development and its relevance to prostate-associated diseases. Additionally, we detail the potential of iPSC-derived prostate organoids for studying human prostate development and disease.


Asunto(s)
Células Madre Pluripotentes Inducidas/citología , Próstata/crecimiento & desarrollo , Hiperplasia Prostática/patología , Neoplasias de la Próstata/patología , Diferenciación Celular , Humanos , Células Madre Pluripotentes Inducidas/patología , Masculino , Organogénesis , Próstata/citología , Próstata/patología , Técnicas de Cultivo de Tejidos
4.
Stem Cells Transl Med ; 9(7): 734-745, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32170918

RESUMEN

Primary culture of human prostate organoids and patient-derived xenografts is inefficient and has limited access to clinical tissues. This hampers their use for translational study to identify new treatments. To overcome this, we established a complementary approach where rapidly proliferating and easily handled induced pluripotent stem cells enabled the generation of human prostate tissue in vivo and in vitro. By using a coculture technique with inductive urogenital sinus mesenchyme, we comprehensively recapitulated in situ 3D prostate histology, and overcame limitations in the primary culture of human prostate stem, luminal and neuroendocrine cells, as well as the stromal microenvironment. This model now unlocks new opportunities to undertake translational studies of benign and malignant prostate disease.


Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Próstata/metabolismo , Animales , Diferenciación Celular , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Embarazo , Ratas , Ratas Sprague-Dawley
5.
Birth Defects Res ; 109(2): 140-152, 2017 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-27768235

RESUMEN

Neurulation, the early embryonic process of forming the presumptive brain and spinal cord, is highly complex and involves hundreds of genes in multiple genetic pathways. Mice have long served as a genetic model for studying human neurulation, and the resulting neural tube defects (NTDs) that arise when neurulation is disrupted. Because mice appear to show mostly single gene inheritance for NTDs and humans show multifactorial inheritance, mice sometimes have been characterized as a simpler model for the identification and study of NTD genes. But are they a simple model? When viewed on different genetic backgrounds, many genes show significant variation in the penetrance and expressivity of NTD phenotypes, suggesting the presence of modifier loci that interact with the target gene to affect the phenotypic expression. Looking at mutations on different genetic backgrounds provides us with an opportunity to explore these complex genetic interactions, which are likely to better emulate similar processes in human neurulation. Here, we review NTD genes known to show strain-specific phenotypic variation. We focus particularly on the gene Cecr2, which is studied using both a hypomorphic and a presumptive null mutation on two different backgrounds: one susceptible (BALB/c) and one resistant (FVB/N) to NTDs. This strain difference has led to a search for genetic modifiers within a region on murine chromosome 19. Understanding how genetic variants alter the phenotypic outcome in NTD mouse models will help to direct future studies in humans, particularly now that more genome wide sequencing approaches are being used. Birth Defects Research 109:140-152, 2017. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Epistasis Genética , Genes Modificadores , Antecedentes Genéticos , Defectos del Tubo Neural/genética , Neurulación/genética , Factores de Transcripción/genética , Animales , Cromosomas de los Mamíferos/química , Cromosomas de los Mamíferos/metabolismo , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Mutación , Tubo Neural/anomalías , Tubo Neural/crecimiento & desarrollo , Tubo Neural/metabolismo , Defectos del Tubo Neural/metabolismo , Defectos del Tubo Neural/patología , Penetrancia , Fenotipo , Factores de Transcripción/deficiencia
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