CSF1R inhibitor-mediated microglial depletion prevents reductions in striatal volume, extracellular matrix alterations, and perineuronal net loss in a mouse model of Huntington’s disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE136158 | GEO | 2019/08/22
REPOSITORIES: GEO
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Project description:C57BL6 mice were subjected to a controlled cortical impact (CCI) to induce a unilateral traumatic brain injury (TBI). After surgery, mice were treated for 5 days with the CSF1R antagonist, PLX3397 or vehicle by daily i.p. injections. PLX3397 is an inhibitor of Colony Stimulating Factor receptor 1 (CSF1R) that leads to a depletion of microglial cells which was confirmed by immunohistochemistry in a subgroup of mice at day 5. Termination of PLX3397 allows for a repopulation of microglial cells which was near complete at 30 days, as assessed by immunofluorescence studies. Perilesional cortical tissue was obtained at the late time point of 30 days after TBI to assess lasting effects of microglia depletion for cortical reorganization that manifested at the transcriptional level. The RNAseq study was done in male and female mice (PLX3397 n = 5 male, 5 female; vehicle n = 5 male, 5 female). Behavioral scores for well-being and motor functions were obatined repeatedly during the observation time. Histology of brain lesion size, indices of neuronal damage and neuroinflammation were obtained at 5d and 30d after TBI. Microglia depletion (PLX3397 treatment) did not reduce the lesion volume and hindered phagocytosis and removal of the hematoma at 5 days, but reduced structural brain damage and neuron loss at 30 days after the injury. Neuroinflammatory markers tended to be lower in PLX3397 treated male than female mice which was associated with better neurological outcome. Overall, CSF1R inhibition provided only subtle lasting beneficial effects.
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Project description:CSF1R inhibitor-mediated microglial depletion prevents reductions in striatal volume, extracellular matrix alterations, and perineuronal net loss in a mouse model of Huntington’s disease
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Project description:Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting.We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.
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Project description:Perineuronal nets (PNNs), which are localized around neurons during development, are specialized forms of neural extracellular matrix with neuroprotective and plasticity-regulating roles. Hyaluronan and proteoglycan link protein 1 (HAPLN1), tenascin-R (TNR) and aggrecan (ACAN) are key elements of PNNs. In diseases characterized by neuritogenesis defects, the expression of these proteins is known to be downregulated, suggesting that PNNs may have a role in neural differentiation.In this study, the mRNA and protein levels of HAPLN1, TNR and ACAN were determined and compared at specific time points of neural differentiation. We used PC12 cells as the in vitro model because they reflect this developmental process.On day 7, the HAPLN1 mRNA level showed a 2.9-fold increase compared to the non-differentiated state. However, the cellular HAPLN1 protein level showed a decrease, indicating that the protein may have roles in neural differentiation, and may be secreted during the early period of differentiation. By contrast, TNR mRNA and protein levels remained unchanged, and the amount of cellular ACAN protein showed a 3.7-fold increase at day 7. These results suggest that ACAN may be secreted after day 7, possibly due to its large amount of post-translational modifications.Our results provide preliminary data on the expression of PNN elements during neural differentiation. Further investigations will be performed on the role of these elements in neurological disease models.
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