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| 2. |
- Delsing, Louise, et al.
(författare)
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Barrier properties and transcriptome expression in human iPSC-derived models of the blood-brain barrier
- 2018
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Ingår i: Stem Cells. - : AlphaMed Press, Inc.. - 1066-5099 .- 1549-4918. ; 36:12, s. 1816-1827
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Tidskriftsartikel (refereegranskat)abstract
- Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of inter-species differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced pluripotent stem cells (iPSCs) can be used to generate relevant cell types to model the BBB with human tissue. We generated a human iPSC-derived model of the BBB that includes endothelial cells in co-culture with pericytes, astrocytes and neurons. Evaluation of barrier properties showed that the endothelial cells in our co-culture model have high transendothelial electrical resistance, functional efflux and ability to discriminate between CNS permeable and non-permeable substances. Whole genome expression profiling revealed transcriptional changes that occur in co-culture, including upregulation of tight junction proteins such as claudins and neurotransmitter transporters. Pathway analysis implicated changes in the WNT, TNF and PI3K-Akt pathways upon co-culture. Our data suggests that co-culture of iPSC-derived endothelial cells promotes barrier formation on a functional and transcriptional level. The information about gene expression changes in co-culture can be used to further improve iPSC-derived BBB models through selective pathway manipulation.
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| 3. |
- Lundin, Anders, et al.
(författare)
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hiPS-Derived Astroglia Model Shows Temporal Transcriptomic Profile Related to Human Neural Development and Glia Competence Acquisition of a Maturing Astrocytic Identity
- 2020
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Ingår i: Advanced Biosystems. - : Wiley. - 2366-7478. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- Astrocyte biology has a functional and cellular diversity only observed in humans. The understanding of the regulatory network governing outer radial glia (RG), responsible for the expansion of the outer subventricular zone (oSVZ), and astrocyte cellular development remains elusive, partly since relevant human material to study these features is not readily available. A human-induced pluripotent stem cell derived astrocytic model, NES-Astro, has been recently developed, with high expression of astrocyte-associated markers and high astrocyte-relevant functionality. Here it is studied how the NES-Astro phenotype develops during specification and its correlation to known RG and astrocyte characteristics in human brain development. It is demonstrated that directed differentiation of neurogenic long-term neuroepithelial stem cells undergo a neurogenic-to-gliogenic competence preferential change, acquiring a glial fate. Temporal transcript profiles of long- and small RNA corroborate previously shown neurogenic restriction by glia-associated let-7 expression. Furthermore, NES-Astro differentiation displays proposed mechanistic features important for the evolutionary expansion of the oSVZ together with an astroglia/astrocyte transcriptome. The NES-Astro generation is a straight-forward differentiation protocol from stable and expandable neuroepithelial stem cell lines derived from iPS cells. Thus, the NES-Astro is an easy-access cell system with high biological relevance for studies of mechanistic traits of glia and astrocyte.
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| 4. |
- Lundin, Anders, et al.
(författare)
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Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models
- 2018
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Ingår i: Stem Cell Reports. - : Cell Press. - 2213-6711. ; 10:3, s. 1030-1045
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Tidskriftsartikel (refereegranskat)abstract
- In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.
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| 5. |
- Rigal, Sophie, et al.
(författare)
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Normoglycemia and physiological cortisone level maintain glucose homeostasis in a pancreas-liver microphysiological system
- 2024
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Ingår i: Communications Biology. - : NATURE PORTFOLIO. - 2399-3642. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with standard in vitro assays. Here, we have connected cell models of key metabolic organs, the pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modeling, we demonstrate that hyperglycemia and high cortisone concentration induce glucose dysregulation in the pancreas-liver microphysiological system (MPS), mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, the pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. Conversely, a physiological culture condition maintains glucose tolerance and beta-cell function. This method was reproducible in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins, as demonstrated with a combined transcriptome and proteome analysis. A human-cell-based pancreas-liver microphysiological system serves as a preclinical platform for studying glucose-insulin homeostasis and disease mechanisms of glucose dysregulation, offering a tool for identifying targets and testing drugs.
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