This SuperSeries is composed of the SubSeries listed below.
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Specimen part, Time
View SamplesR1 mESCs were trasnfected with siRNAs against CnAb1 or Control (Luciferase) using Lipofectamine. mRNA was extracted 48 hours using Qiagen RNAeasy Mini kit
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Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
Specimen part
View SamplesMyeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
Specimen part
View SamplesPPARg is a nuclear receptor that plays an important role in lipid metabolism, homeostasis and immunity. Microarray analysis of gene expression was performed in macrophages from WT and PPARg KO mice. Differentially expressed genes were selected for further analysis.
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Specimen part
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