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- Alexander, Jes, et al.
(författare)
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Multimodal single-cell analysis reveals distinct radioresistant stem-like and progenitor cell populations in murine glioma
- 2020
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Ingår i: GLIA. - : Wiley. - 0894-1491 .- 1098-1136. ; 68:12, s. 2486-2502
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Tidskriftsartikel (refereegranskat)abstract
- Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells. In these analyses, mouse models of glioma have been used to understand the biology of this disease and therapeutic responses, including the radiation response. We present combined SP analysis and single-cell RNA sequencing of genetically-engineered mouse models of glioma to show a time course of cellular response to radiation. We identify and characterize two distinct tumor cell populations that are inherently radioresistant and also distinct effects of radiation on immune cell populations within the tumor microenvironment.
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- Goncalves, Nadia P., et al.
(författare)
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Schwann cell p75 neurotrophin receptor modulates small fiber degeneration in diabetic neuropathy
- 2020
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Ingår i: Glia. - : WILEY. - 0894-1491 .- 1098-1136. ; 68:12, s. 2725-2743
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic neuropathy has an incidence as high as 50% of diabetic patients and is characterized by damage to neurons, Schwann cells and blood vessels within the peripheral nervous system. The low-affinity neurotrophin receptor p75 (p75(NTR)), particularly expressed by the Schwann cells in the peripheral nerve, has previously been reported to play a role in developmental myelination and cell survival/death. Increased levels of p75(NTR), in the endoneurium and plasma from diabetic patients and rodent models of disease, have been observed, proposing that this receptor might be involved in the pathogenesis of diabetic neuropathy. Therefore, in this study, we addressed this hypothesis by utilizing a mouse model of selective nerve growth factor receptor (Ngfr) deletion in Schwann cells (SC-p75(NTR)-KO). Electron microscopy of sciatic nerves from mice with high fat diet induced obesity demonstrated how loss of Schwann cell-p75(NTR)aggravated axonal atrophy and loss of C-fibers. RNA sequencing disclosed several pre-clinical signaling alterations in the diabetic peripheral nerves, dependent on Schwann cell p75(NTR)signaling, specially related with lysosome, phagosome, and immune pathways. Morphological and biochemical analyses identified abundant lysosomes and autophagosomes in the C-fiber axoplasm of the diabetic SC-p75(NTR)-KO nerves, which together with increased Cathepsin B protein levels corroborates gene upregulation from the phagolysosomal pathways. Altogether, this study demonstrates that Schwann cell p75(NTR)deficiency amplifies diabetic neuropathy disease by triggering overactivation of immune-related pathways and increased lysosomal stress.
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- Kaplan, Lew, et al.
(författare)
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Retinal regions shape human and murine Müller cell proteome profile and functionality
- 2023
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Ingår i: GLIA. - : Wiley. - 0894-1491 .- 1098-1136. ; 71:2, s. 391-414
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Tidskriftsartikel (refereegranskat)abstract
- The human macula is a highly specialized retinal region with pit-like morphology and rich in cones. How Müller cells, the principal glial cell type in the retina, are adapted to this environment is still poorly understood. We compared proteomic data from cone- and rod-rich retinae from human and mice and identified different expression profiles of cone- and rod-associated Müller cells that converged on pathways representing extracellular matrix and cell adhesion. In particular, epiplakin (EPPK1), which is thought to play a role in intermediate filament organization, was highly expressed in macular Müller cells. Furthermore, EPPK1 knockout in a human Müller cell-derived cell line led to a decrease in traction forces as well as to changes in cell size, shape, and filopodia characteristics. We here identified EPPK1 as a central molecular player in the region-specific architecture of the human retina, which likely enables specific functions under the immense mechanical loads in vivo.
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