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1.
Nat Rev Endocrinol ; 19(4): 232-248, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36670309

RESUMEN

Our understanding of diabetes mellitus has benefited from a combination of clinical investigations and work in model organisms and cell lines. Organoid models for a wide range of tissues are emerging as an additional tool enabling the study of diabetes mellitus. The applications for organoid models include studying human pancreatic cell development, pancreatic physiology, the response of target organs to pancreatic hormones and how glucose toxicity can affect tissues such as the blood vessels, retina, kidney and nerves. Organoids can be derived from human tissue cells or pluripotent stem cells and enable the production of human cell assemblies mimicking human organs. Many organ mimics relevant to diabetes mellitus are already available, but only a few relevant studies have been performed. We discuss the models that have been developed for the pancreas, liver, kidney, nerves and vasculature, how they complement other models, and their limitations. In addition, as diabetes mellitus is a multi-organ disease, we highlight how a merger between the organoid and bioengineering fields will provide integrative models.


Asunto(s)
Diabetes Mellitus , Células Madre Pluripotentes , Humanos , Organoides/metabolismo , Diabetes Mellitus/metabolismo , Páncreas , Hígado
2.
Nat Commun ; 13(1): 6255, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-36271049

RESUMEN

Diabetes is a multifactorial disorder characterized by loss or dysfunction of pancreatic ß-cells. ß-cells are heterogeneous, exhibiting different glucose sensing, insulin secretion and gene expression. They communicate with other endocrine cell types via paracrine signals and between ß-cells via gap junctions. Here, we identify the importance of signaling between ß-cells via the extracellular signal WNT4. We show heterogeneity in Wnt4 expression, most strikingly in the postnatal maturation period, Wnt4-positive cells, being more mature while Wnt4-negative cells are more proliferative. Knock-out in adult ß-cells shows that WNT4 controls the activation of calcium signaling in response to a glucose challenge, as well as metabolic pathways converging to lower ATP/ADP ratios, thereby reducing insulin secretion. These results reveal that paracrine signaling between ß-cells is important in addition to gap junctions in controling insulin secretion. Together with previous reports of WNT4 up-regulation in obesity our observations suggest an adaptive insulin response coordinating ß-cells.


Asunto(s)
Señalización del Calcio , Insulinas , Glucosa/metabolismo , Adenosina Trifosfato/metabolismo , Insulinas/metabolismo , Adenosina Difosfato/metabolismo
3.
Cell Rep ; 31(8): 107677, 2020 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-32460029

RESUMEN

Cell polarity is essential for the architecture and function of numerous epithelial tissues. Here, we show that apical restriction of planar cell polarity (PCP) components is necessary for the maintenance of epithelial integrity. Using the mammalian pancreas as a model, we find that components of the core PCP pathway, such as the transmembrane protein Van Gogh-like (VANGL), become apically restricted over a period of several days. Expansion of VANGL localization to the basolateral membranes of progenitors leads to their death and disruption of the epithelial integrity. VANGL basolateral expansion does not affect apico-basal polarity but acts in the cells where Vangl is mislocalized by reducing Dishevelled and its downstream target ROCK. This reduction in ROCK activity culminates in progenitor cell egression, death, and eventually pancreatic hypoplasia. Thus, precise spatiotemporal modulation of VANGL-dependent PCP signaling is crucial for proper pancreatic morphogenesis.


Asunto(s)
Proteínas de la Membrana/metabolismo , Conductos Pancreáticos/ultraestructura , Animales , Membrana Celular , Polaridad Celular , Epitelio , Ratones
4.
PLoS Biol ; 16(7): e2002842, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30048442

RESUMEN

The mammalian pancreas is a branched organ that does not exhibit stereotypic branching patterns, similarly to most other glands. Inside branches, it contains a network of ducts that undergo a transition from unconnected microlumen to a mesh of interconnected ducts and finally to a treelike structure. This ductal remodeling is poorly understood, both on a microscopic and macroscopic level. In this article, we quantify the network properties at different developmental stages. We find that the pancreatic network exhibits stereotypic traits at each stage and that the network properties change with time toward the most economical and optimized delivery of exocrine products into the duodenum. Using in silico modeling, we show how steps of pancreatic network development can be deconstructed into two simple rules likely to be conserved for many other glands. The early stage of the network is explained by noisy, redundant duct connection as new microlumens form. The later transition is attributed to pruning of the network based on the flux of fluid running through the pancreatic network into the duodenum.


Asunto(s)
Conductos Pancreáticos/embriología , Animales , Líquidos Corporales/metabolismo , Colforsina/farmacología , Simulación por Computador , Desarrollo Embrionario , Femenino , Procesamiento de Imagen Asistido por Computador , Ratones Endogámicos ICR , Conductos Pancreáticos/anatomía & histología , Factores de Tiempo
5.
J Cell Sci ; 131(14)2018 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-30054310

RESUMEN

During growth, homeostasis and regeneration, stem cells are exposed to different energy demands. Here, we characterise the metabolic pathways that mediate the commitment and differentiation of mouse skeletal muscle stem cells, and how their modulation can influence the cell state. We show that quiescent satellite stem cells have low energetic demands and perturbed oxidative phosphorylation during ageing, which is also the case for cells from post-mortem tissues. We show also that myogenic fetal cells have distinct metabolic requirements compared to those proliferating during regeneration, with the former displaying a low respiration demand relying mostly on glycolysis. Furthermore, we show distinct requirements for peroxisomal and mitochondrial fatty acid oxidation (FAO) in myogenic cells. Compromising peroxisomal but not mitochondrial FAO promotes early differentiation of myogenic cells. Acute muscle injury and pharmacological block of peroxisomal and mitochondrial FAO expose differential requirements for these organelles during muscle regeneration. Taken together, these observations indicate that changes in myogenic cell state lead to significant alterations in metabolic requirements. In addition, perturbing specific metabolic pathways impacts on myogenic cell fates and the regeneration process.


Asunto(s)
Desarrollo de Músculos , Músculo Esquelético/crecimiento & desarrollo , Células Madre/citología , Células Madre/metabolismo , Animales , Proliferación Celular , Ácidos Grasos/metabolismo , Ratones , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Oxidación-Reducción , Peroxisomas/metabolismo , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/metabolismo
6.
Skelet Muscle ; 8(1): 19, 2018 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-29875011

RESUMEN

After publication of this article [1], the authors noted that the legends for supplementary files Figures S3 and S4 were truncated in the production process, therefore lacking some information concerning these Figures. The complete legends are included in this Correction. The authors apologize for any inconvenience that this might have caused.

7.
Skelet Muscle ; 7(1): 28, 2017 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-29273087

RESUMEN

BACKGROUND: Skeletal muscle satellite (stem) cells are quiescent in adult mice and can undergo multiple rounds of proliferation and self-renewal following muscle injury. Several labs have profiled transcripts of myogenic cells during the developmental and adult myogenesis with the aim of identifying quiescent markers. Here, we focused on the quiescent cell state and generated new transcriptome profiles that include subfractionations of adult satellite cell populations, and an artificially induced prenatal quiescent state, to identify core signatures for quiescent and proliferating. METHODS: Comparison of available data offered challenges related to the inherent diversity of datasets and biological conditions. We developed a standardized workflow to homogenize the normalization, filtering, and quality control steps for the analysis of gene expression profiles allowing the identification up- and down-regulated genes and the subsequent gene set enrichment analysis. To share the analytical pipeline of this work, we developed Sherpa, an interactive Shiny server that allows multi-scale comparisons for extraction of desired gene sets from the analyzed datasets. This tool is adaptable to cell populations in other contexts and tissues. RESULTS: A multi-scale analysis comprising eight datasets of quiescent satellite cells had 207 and 542 genes commonly up- and down-regulated, respectively. Shared up-regulated gene sets include an over-representation of the TNFα pathway via NFKß signaling, Il6-Jak-Stat3 signaling, and the apical surface processes, while shared down-regulated gene sets exhibited an over-representation of Myc and E2F targets and genes associated to the G2M checkpoint and oxidative phosphorylation. However, virtually all datasets contained genes that are associated with activation or cell cycle entry, such as the immediate early stress response genes Fos and Jun. An empirical examination of fixed and isolated satellite cells showed that these and other genes were absent in vivo, but activated during procedural isolation of cells. CONCLUSIONS: Through the systematic comparison and individual analysis of diverse transcriptomic profiles, we identified genes that were consistently differentially expressed among the different datasets and shared underlying biological processes key to the quiescent cell state. Our findings provide impetus to define and distinguish transcripts associated with true in vivo quiescence from those that are first responding genes due to disruption of the stem cell niche.


Asunto(s)
Diferenciación Celular , Células Satélite del Músculo Esquelético/metabolismo , Transcriptoma , Animales , Bases de Datos Factuales , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones
8.
Cell Metab ; 20(6): 1038-48, 2014 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-25456740

RESUMEN

Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone-inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression.


Asunto(s)
Músculo Esquelético/citología , Células Madre/citología , Hormonas Tiroideas/metabolismo , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/metabolismo , Transducción de Señal/fisiología
9.
Cell Rep ; 7(4): 961-70, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24836002

RESUMEN

Cells of several metazoan species have been shown to non-randomly segregate their DNA such that older template DNA strands segregate to one daughter cell. The mechanisms that regulate this asymmetry remain undefined. Determinants of cell fate are polarized during mitosis and partitioned asymmetrically as the spindle pole orients during cell division. Chromatids align along the pole axis; therefore, it is unclear whether extrinsic cues that determine spindle pole position also promote non-random DNA segregation. To mimic the asymmetric divisions seen in the mouse skeletal stem cell niche, we used micropatterns coated with extracellular matrix in asymmetric and symmetric motifs. We show that the frequency of non-random DNA segregation and transcription factor asymmetry correlates with the shape of the motif and that these events can be uncoupled. Furthermore, regulation of DNA segregation by cell adhesion occurs within a defined time interval. Thus, cell adhesion cues have a major impact on determining both DNA segregation patterns and cell fates.


Asunto(s)
Segregación Cromosómica/fisiología , ADN/metabolismo , Músculo Esquelético/fisiología , Células Madre/fisiología , Animales , Adhesión Celular/fisiología , Diferenciación Celular/fisiología , División Celular/fisiología , ADN/genética , Ratones , Ratones Transgénicos , Músculo Esquelético/citología , Células Madre/citología
10.
Semin Cell Dev Biol ; 24(8-9): 627-42, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23680492

RESUMEN

The semi-conservative nature of DNA replication has suggested that identical DNA molecules within chromatids are inherited by daughter cells after cell division. Numerous reports of non-random DNA segregation in prokaryotes and eukaryotes suggest that this is not always the case, and that epigenetic marks on chromatids, if not the individual DNA strands themselves, could have distinct signatures. Their selective distribution to daughter cells provides a novel mechanism for gene and cell fate regulation by segregating chromatids asymmetrically. Here we highlight some examples and potential mechanisms that can regulate this process. We propose that cellular asymmetry is inherently present during each cell division, and that it provides an opportunity during each cell cycle for moderating cell fates.


Asunto(s)
División Celular Asimétrica , Linaje de la Célula , ADN/metabolismo , Células Madre/citología , Células Madre/metabolismo , Animales , Segregación Cromosómica , Humanos , Moldes Genéticos
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