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KMT2C deficiency enhances HSC mobilization and granulocyte bias in response to G-CSF

ABSTRACT: KMT2C deficiency enhances HSC mobilization and granulocyte bias in response to G-CSF

PROVIDER: PRJNA1020192 | ENA |

REPOSITORIES: ENA

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	SRR29490500_1.fastq.gz	Fastqsanger.gz
	SRR29490500_2.fastq.gz	Fastqsanger.gz
	SRR29490501_1.fastq.gz	Fastqsanger.gz
	SRR29490501_2.fastq.gz	Fastqsanger.gz

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KMT2C deficiency enhances HSC mobilization and granulocyte bias in response to G-CSF

Project description:single cell RNA-seq/CITE-seq analysis of bone marrow cells from wild type and Kmt2c-deleted mice

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Project description:Granulocyte-colony stimulating factor (G-CSF) is used to boost granulocyte counts in immunocompromised patients, but its effects on the immune system may be counter productive. We tested the hypothesis that G-CSF mobilized peripheral blood stem cell (PBSC) products are immunologically down regulated based on gene microarray analysis. Ten peripheral blood samples from normal donors for allogeneic PBSC transplantation were obtained before and after administration of G-CSF and tested on Affymetrix Human U133 Plus 2.0 GeneChip® microarrays. Significant changes in gene expression after G-CSF mobilization were reported by controlling the false discovery rate at 5%. Immune-related genes were isolated from the data set and categorized according to probe set annotations and a thorough, independent literature search. We found that G-CSF up-regulated inflammatory and neutrophil activation pathway gene expression; however, adaptive immune-related gene expression, such as antigen presentation, co-stimulation, T cell activation and cytolytic effector pathways, were generally down-regulated. Thus, despite significant increases in stem cells, lymphocytes and antigen presenting cells, G-CSF mobilized PBSC allografts exhibit a suppressive adaptive immune-related gene expression profile. Our data provides an explanation for the potentially immunosuppressive effects observed after G-CSF administration. Keywords: PBSCT, G-CSF, microarray, gene expression

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G-CSF plus AMD3100 mobilization in adult patients with beta-thalassemia results in effective mobilization of CD34+ cells with primitive signatures

Project description:Successful gene therapy for Î²-thalassemia requires optimal numbers of autologous gene-transduced hematopoietic progenitors stem cells (HPSC) with high repopulating capacity and mobilization is the optimal approach for achieving this goal. We performed a clinical study to investigate safety and efficacy of G-CSF+AMD3100 mobilization in four adult with Î²-thalassemia to reach a cell dose of â¥8x106 CD34+cells/Kg and to characterize the CD34+cell populations mobilized before and after plerixafor administration. The procedure resulted well-tolerated in all patients. Three of the four patients reached the target cell dose or more in single-apheresis collections, even one patient where a significant dose reduction of G-CSF was imposed due to early hyperleukocytosis. A significant increase in the number of circulating CD34+ cells/Âµl (12.1Â± 8.2 fold), and in the frequency of the more primitive CD34+/CD133+/CD38- cells (1.7Â±0.7 fold) was unanimously observed after AMD3100 addiction. Intraindividual comparison of gene expression profile of CD34+ cells mobilized with G-CSF versus G-CSF+ AMD3100 highlighted a different expression pattern of genes involved in the processes of HSC/stroma adhesion, homing, cell motility and transcription regulation. Overall, the safety profile, the yield, and the expression of genes that potentially promote superior engraftment depict G-CSF+AMD3100 mobilized HSC as optimal graft source for Î²-thalassemia gene therapy One experiment performed on purified CD34+ PBPC of the same patient 1 after mobilization with G-CSF + Plerixafor , and after mobilization with G-CSF alone. Universal Human Reference RNA (Stratagene, La Jolla, CA), was used as reference.

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Central nervous system muscarinic receptor type-1 primes HSC mobilization from bone marrow via glucocorticoid-mediated relay

Project description:Here we show that muscarinic type-1 (Chrm1) signaling in the central nervous system (CNS) promotes G-CSF-elicited HSC migration from the BM. Blockade of Chrm1 in the CNS, but not the periphery, reduced HSC mobilization. In Chrm1−⁄− mice, reduced mobilization was rescued by wild-type parabionts, suggesting the contribution of a soluble factor. We found that corticosterone levels were dramatically reduced in the BM, and its exogenous administration normalized the mobilization deficit of Chrm1−⁄− animals. Chrm1−⁄− HSCs have reduced nuclear glucocorticoid receptors (Nr3c1) and alterations in the expression of actin-organizing molecules. Polymerized actin formation and HSC mobilization are also impaired in mice harboring Nr3c1-deficient hematopoietic cells.

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Gene regulation by restoration of KMT2C in human colorectal cancer cells HCT116 and RKO

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Modification of T cell responses by stem cell mobilization requires direct signalling of the T cell by G-CSF and IL-10

Project description:The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the haematopoietic or non-haematopoietic compartments were wild-type (WT), IL-10–/–, G-CSFR–/– or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after with G-CSF mobilization required direct signalling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4+CD25+ regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell’s ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

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