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- Lee, S. D., et al.
(författare)
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IDOL regulates systemic energy balance through control of neuronal VLDLR expression
- 2019
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:11
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Tidskriftsartikel (refereegranskat)abstract
- Liver X receptors limit cellular lipid uptake by stimulating the transcription of inducible degrader of the low-density lipoprotein receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of dietinduced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose tissue, endothelium, intestine, and skeletal muscle) but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to the control of metabolism. Finally, we identified very low-density lipoprotein receptor (VLDLR) rather than low-density lipoprotein receptor (LDLR) as the primary mediator of the effects of IDOL on energy balance. These data identify a role for the neuronal IDOL-VLDLR pathway in metabolic homoeostasis and diet-induced obesity.
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- Li, S. Y., et al.
(författare)
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Universal toxin-based selection for precise genome engineering in human cells
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Prokaryotic restriction enzymes, recombinases and Cas proteins are powerful DNA engineering and genome editing tools. However, in many primary cell types, the efficiency of genome editing remains low, impeding the development of gene- and cell-based therapeutic applications. A safe strategy for robust and efficient enrichment of precisely genetically engineered cells is urgently required. Here, we screen for mutations in the receptor for Diphtheria Toxin (DT) which protect human cells from DT. Selection for cells with an edited DT receptor variant enriches for simultaneously introduced, precisely targeted gene modifications at a second independent locus, such as nucleotide substitutions and DNA insertions. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation. Toxin-based selection works in both cancer-transformed and non-transformed cells, including human induced pluripotent stem cells and human primary T-lymphocytes, as well as it is applicable also in vivo, in mice with humanized liver. This work represents a flexible, precise, and efficient selection strategy to engineer cells using CRISPR-Cas and base editing systems. Genome engineering in cell lines or human stem cells often has poor efficiency, limiting the development of research and therapeutic applications. Here, the authors use a toxin-based selection system for precise bi-allelic engineering in cells and in vivo.
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- Neumann, Susanne, et al.
(författare)
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Cranial irradiation at early postnatal age impairs stroke-induced neural stem/progenitor cell response in the adult brain
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Cranial irradiation (IR) is commonly used to treat primary brain tumors and metastatic diseases. However, cranial IR-treated patients often develop vascular abnormalities later in life that increase their risk for cerebral ischemia. Studies in rodents have demonstrated that IR impairs maintenance of the neural stem/precursor cell (NSPC) pool and depletes neurogenesis. We and others have previously shown that stroke triggers NSPC proliferation in the subventricular zone and migration towards the stroke-injured neocortex. Whether this response is sustained in the irradiated brain remains unknown. Here, we demonstrate that cranial IR in mice at an early postnatal age significantly reduced the number to neuronal progenitors responding to cortical stroke in adults. This was accompanied by a reduced number of microglia/macrophages in the peri-infarct cortex; however, the astrocytic response was not altered. Our findings indicate that IR impairs the endogenous repair capacity in the brain in response to stroke, hence pointing to another side effect of cranial radiotherapy which requires further attention.
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- Osman, Ahmed M, et al.
(författare)
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Long-term stimulation of neural progenitor cell migration after cortical ischemia in mice.
- 2011
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Ingår i: Stroke; a journal of cerebral circulation. - 1524-4628. ; 42:12, s. 3559-65
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Tidskriftsartikel (refereegranskat)abstract
- Cortical ischemia induces neural progenitor cell migration toward the injury site; however, whether these cells are capable of maintaining the migratory response for a longer period after injury remains uncertain. METHODS: We analyzed progenitor migration up to 1 year after induction of photothrombotic stroke to the mouse neocortex. Migrating progenitors identified as doublecortin positive cells (DCX+) were assessed using the immunohistochemistry and immunofluorescence. The thymidine analogues chlorodeoxyuridine and iododeoxyuridine were used to birth-date the progenitor cells. RESULTS: In the striatum, we detected elevated numbers of DCX+ cells up to 6 weeks postlesion. In the corpus callosum and the peri-infarct cortex (Ctx), DCX+ cell numbers were increased up to 1 year. The orientation of the migrating progenitors was mostly aligned with the corpus callosum fiber tract at all time points; however, in the Ctx, they aligned parallel to the infarct border. The injured cortex continuously receives new progenitors up to 1 year after lesion. Cells born after lesion did not become mature neurons, although a portion of the migrating progenitors showed initial signs of differentiation into neurons. CONCLUSIONS: Neural progenitors might have a role in brain plasticity after cortical stroke, especially considering the prolonged window of migratory responses of up to 1 year after stroke lesion.
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