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DNA damage-induced HSPC failure depends on ROS accumulation downstream of IFN-1 signaling and Bid mobilization

ABSTRACT: Targeted mouse mutants with inactivated Mixed-Lineage-Leukemia-5 (Mll5, MGI:1924825) alleles exhibit numerical, cell cycle and functional abnormalities in their hematopoietic stem and progenitor cell (HSPC) compartments, including hyper-proliferation of otherwise quiescent hematopoietic stem cells, lack of long-term reconstitution potential and profound radiation sensitivity. Most of the HSPC defects are secondary to increased levels of DNA damage and intracellular accumulation of reactive oxygen species (ROS). To obtain first insights into underlying molecular mechanisms, we performed Affymetrix gene chip analysis using total RNA isolated from FACS-sorted Lin-Sca1+Kit+ (LSK) cells of Mll5+/+ and Mll5-/- mice, both with and without prior long-term treatment with the ROS quencher N-Acetyl-L-Cysteine (NAC). As key finding, microarray data revealed elevated hybridization signals for several transcripts of known or putative IFN-1 target genes in LSK cells from Mll5-/- mice irrespective of NAC-treatment. In fact, comprehensive gene set enrichment analysis identified a number of gene sets closely associated with interferon responses that were significantly affected in Mll5-/- LSK cells. RNA was isolated from FACS-sorted Lin-Sca1+Kit+ (LSK) cells of Mll5+/+ and Mll5-/- mice, both with and without prior long-term treatment with the ROS quencher N-Acetyl-L-Cysteine (NAC)

ORGANISM(S): Mus musculus

SUBMITTER: Medhanie Mulaw

PROVIDER: E-GEOD-85076 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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DNA damage-induced HSPC failure depends on ROS accumulation downstream of IFN-1 signaling and Bid mobilization

Project description:Targeted mouse mutants with inactivated Mixed-Lineage-Leukemia-5 (Mll5, MGI:1924825) alleles exhibit numerical, cell cycle and functional abnormalities in their hematopoietic stem and progenitor cell (HSPC) compartments, including hyper-proliferation of otherwise quiescent hematopoietic stem cells, lack of long-term reconstitution potential and profound radiation sensitivity. Most of the HSPC defects are secondary to increased levels of DNA damage and intracellular accumulation of reactive oxygen species (ROS). To obtain first insights into underlying molecular mechanisms, we performed Affymetrix gene chip analysis using total RNA isolated from FACS-sorted Lin-Sca1+Kit+ (LSK) cells of Mll5+/+ and Mll5-/- mice, both with and without prior long-term treatment with the ROS quencher N-Acetyl-L-Cysteine (NAC). As key finding, microarray data revealed elevated hybridization signals for several transcripts of known or putative IFN-1 target genes in LSK cells from Mll5-/- mice irrespective of NAC-treatment. In fact, comprehensive gene set enrichment analysis identified a number of gene sets closely associated with interferon responses that were significantly affected in Mll5-/- LSK cells.

2016-08-02 | GSE85076 | GEO

The effects of NAC on gene expression in Nkx3.1-/- mouse prostate

Project description:We tested the effects of the antioxidant NAC (N-Acetyl-Cysteine) on gene expression in Nkx3.1-deficient mouse prostate. Mice that were homozygous null for Nkx3.1 were given NAC or plain water ad libidum for 13 weeks after weaning. Prostates were collected, RNA was harvested and reverse transcribed, and cDNA was hybridized to Affy Mouse Gene 1.0 ST microarrays.

2012-10-23 | E-GEOD-40352 | biostudies-arrayexpress

Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation

Project description:Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. In the present study, we asked whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), we examined the impact of 3R4F as a reference CSE, and HSPC-supporting function was determined. Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. 3R4F-exposed MSCs also developed impaired HSPC-supportive function, as confirmed by colony forming unit (CFU) assays and HSPC transplantation into NSG mice, and were further restored by the ROS inhibitor N-acetyl-l-cysteine (NAC). Finally, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. In conclusion, these findings indicate that exposure to CSE reduces the HSPC-supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

2024-01-17 | GSE253105 | GEO

Transcription profiling of human NHEK cells response to 2mM N-Acetyl-L-cystein (NAC) treatment - 1,12, 24 hour time-series

Project description:NHEK cells were plated at a density of 8 x 10 000/cm2 and the cell cultures were grown for 24 hours before addition of 2 mM N-Acetyl-L-Cystein. RNA obtained from cultures grown for 1, 12 and 24 hrs after NAC treatment were compared to RNA from untreated cells at the corresponding time points. I.e 1 hour NAC treated vs 1 hour untreated cells etc. Each EXTRACT represents an individual mRNA extraction and subsequent cDNA synthesis from a batch of totalRNA originating from one cellculture dish.

2005-07-15 | E-MEXP-146 | biostudies-arrayexpress

The effects of NAC on gene expression in Nkx3.1-/- mouse prostate

Project description:We tested the effects of the antioxidant NAC (N-Acetyl-Cysteine) on gene expression in Nkx3.1-deficient mouse prostate.

2012-10-23 | GSE40352 | GEO

Transcription profiling of human colon carcinoma cells Caco-2 response to N-acetyl-L-cystein (10 mM) (1,12 and 24 hour time-series)

Project description:Caco-2 human colon carcinoma cells were seeded at a density of 9 x 10 000 cells/cm2 and the cell cultures were grown for 24 hours before addition of 10 mM N-Acetyl-L-Cystein. RNA obtained from cultures grown for 1, 12 and 24 hrs after NAC treatment were compared to RNA from untreated cells at the corresponding time points. I.e 1 hour NAC treated vs 1 hour untreated cells etc. Each "SAMPLE" represents a biological replicate (i.e. separate cellcultures treated similarily) although I have given identical SAMPLE numbers in pairs.

2005-07-15 | E-MEXP-147 | biostudies-arrayexpress

N-Acetyl-L-cysteine facilitates tendon repair and promotes the tenogenic differentiation of tendon stem/progenitor cells by enhancing the integrin α5/β1/PI3K/AKT signaling

Project description:N-acetyl-L-cysteine (NAC) is a potent antioxidant. However, how NAC affects the biological functions of tendon stem/progenitor cells (TSPCs) and tendon repair has not been clarified.The effect of NAC on gene transcription in TSPCs was analyzed by transcriptomes and bioinformatics.

2022-11-18 | GSE218038 | GEO

The enzyme paraoxonase-2 modulates hematopoiesis through redox signaling

Project description:Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow (BM) niches with low levels of oxygen and reactive oxygen species (ROS). ROS enhancement results in differentiation of LT-HSCs. Redox disturbances are involved in BM failure and leukemia. Paraoxonase-2 (PON2) has been shown to be important for ROS control. However, the role of PON2 in the hematopoietic system has not been addressed. Analysis of young mice with inactivated Pon2 gene (Pon2-/- mice; 3 months) revealed changes in quantity of hematopoietic stem and progenitor cells (HSPCs), which indicate changes in cell differentiation. Experiments with aged PON2-/- mice (>9 months) showed alterations of the HSPC compartment indicating changed self-renewal ability of HSCs and myeloid skewing. Reciprocal BM transplantation reveals cell intrinsic as well as extrinsic phenotypes. We observed markedly enhanced superoxide levels in BM as well as slightly enhanced total ROS level in short term (ST)-HSCs and multipotent progenitor cells (MPPs) of young mice. In aged mice, total ROS level was slightly increased in all 3 fractions of the Lin-, Sca1+, ckit+ (LSK) population. No changes in the amount of DNA double-strand breaks in LSK cells and decreased apoptosis rates in LT-HSCs of young as well as LT- and ST-HSCs of aged PON2-/- mice were seen, indicating a strong compensation mechanism. Changes of gene expression in PON2-/- LT-HSCs identified by RNA sequencing strengthened our conclusions. Additionally, competitive and serial bone marrow transplantation experiments exposed advantages of PON2-/- BMCs in multi-lineage reconstitution. Collectively, these analyses propose PON2 as crucial redox control enzyme in HSCs.

2021-07-20 | GSE122553 | GEO

LBP resists hepatic oxidative stress by regulating LD homeostasis

Project description:we explored the novel role of Lipopolysaccharide-binding protein (LBP) as an anti-oxidant, which can capture unsaturated triglyceride (TG) into LDs to avoid lipid peroxidation. Oxidative stress upregulates LBP level and promotes LDs growth via the LBP/TG phase transition. Upon N-Acetyl-L-cysteine (NAC) elimination of ROS, LBP is exported from LD along with PRDX4, resulting in an increase in phospholipid synthesis. Chronic stress causes LBP upregulation and leads to obesity, which can be rescued by NAC treatment in vivo. These results support that LBP maintains homeostasis by coupling lipid metabolism and redox signal, which provides insights into redox medicine that mitigate stress-induced metabolic dysfunction.

2024-04-10 | PXD040940 | Pride

Transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue

Project description:Trichloroethylene (TCE) is a persistent and pervasive environmental contaminant. N-acetyl cysteine (NAC) is an antioxidant that may reduce TCE effects. Pregnant Wistar rats were exposed to 480 mg TCE mg/kg/day, 200 mg/kg/day NAC or co-exposure with both chemicals via ingestion (mini vanilla wafer) on gestation days 6-16 (tissue collection day). TCE- and/or NAC-induced changes to gene expression were evaluated in male and female rat placentae.

2022-06-01 | GSE168232 | GEO

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