Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA sequencing of bone marrow hematopoietic progenitor and Gr1+/Mac1+ cells derived from Diap1 wild type, heterozygous, and knockout mice.

ABSTRACT: The goal of the experiment was to study the aberrant signalling pathways due to loss of or haploinsufficiency of Diap1 protein. We found that LPS receptor transcript is highly expressed in Diap1 deficient Gr1+/Mac1+ cells but not in Lin- cells, suggesting a role for Diap1 in determining the normal morphology of committed Gr1+/Mac1+ cells. Examination of gene expression profiles of bone marrow hematopoietic progenitor and Gr1+/Mac1+ myeloid cells from Diap1 wild type, heterozygous, and knockout mice.

ORGANISM(S): Mus musculus

SUBMITTER: Peng Ji

PROVIDER: E-GEOD-45597 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. RNA sequencing of oligodendrocyte progenitor cells treated with vehicle, miconazole or clobetasol for 0, 2, 6, or 12 hours. Cells were plated 1.5 hours prior to addition of drug.

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RNA sequencing of bone marrow hematopoietic progenitor and Gr1+/Mac1+ cells derived from Diap1 wild type, heterozygous, and knockout mice.

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