Single Cell RNA sequencing of CD11b+Gr1+ cells from the bone marrow of young and aged mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275786 | GEO | 2024/09/01
REPOSITORIES: GEO
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Project description:An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater bone resorption capacity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was a 3-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database. CD38 regulates NAD+ availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in Cd38 expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging.
2024-09-16 | GSE252129 | GEO
Project description:The gene expression of murine splenic myeloid derived suppressor cells treated with Tff2 is characterized. The motivation of the study originates in the fact that Gr1+Cd11b+ myeloid-derived suppressor cells (MDSCs), which resemble immature myeloid cells (IMCs), expand during cancer in response to inflammatory cytokines and accumulate in the spleen. MDSCs promote neoplastic progression through their suppression of anti-tumourigenic cytotoxic T-cells. MDSCs are also rapidly expanded following acute insults, but in cancer as opposed to acute inflammation, MDSCs persist. It is now recognized that a vagally-mediated, anti-inflammatory reflex arc promoting acetylcholine secretion by Cd4+ (Cd44hiSelllo) T cells, is necessary for a return to homeostasis after an acute insult. Failure of this restorative neural circuit might contribute to unabated procarcinogenic inflammation, with the chronic expansion of MDSCs driving carcinogenesis. Trefoil factor 2 (Tff2) is a secreted anti-inflammatory peptide produced by both epithelial cells and a small subset of splenic T cell. In this study, we show that splenic Tff2 is induced in vagally-modulated memory T cells to suppress the expansion of MDSCs in response to chemical and carcinogenic injury. Deletion of Tff2 interrupts this anti-inflammatory neural arc and leads to expanded MDSCs and a dramatically increased incidence of colorectal cancer. Tff2 directly suppresses proliferation of myeloid progenitors, in a large part through upregulation of cell-bound Apolipoprotein E (ApoE), which has previously been shown to suppress proliferation of haematopoietic stem and progenitor cells. The predisposition to inflammation-associated cancer can be rescued through transgenic overexpression of splenic Tff2, adenoviral transfer of Tff2 expression or transplantation of Tff2-expressing haematopoietic cells. Thus, Tff2 production in memory T cells, is regulated by the vagus nerve, plays a central role in arresting procarcinogenic MDSC proliferation, and offers a novel approach to the prevention and treatment. A. Gr1+Cd11b+ splenic cells from Tff2-/- mice treated with Csf2 (n=4). B. Gr1+Cd11b+ splenic cells from Tff2-/- mice treated with Tff2 and Csf2 (n=4).
2016-05-30 | E-GEOD-47596 | biostudies-arrayexpress
Project description:In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. While the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have not yet been characterized. Gene expression profiling revealed that aged human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, function, and gene expression profile of human HSC are significantly similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process. In order to elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared to young HSC.
2011-11-11 | E-GEOD-32719 | biostudies-arrayexpress
Project description:The gene expression of murine splenic myeloid derived suppressor cells treated with Tff2 is characterized. The motivation of the study originates in the fact that Gr1+Cd11b+ myeloid-derived suppressor cells (MDSCs), which resemble immature myeloid cells (IMCs), expand during cancer in response to inflammatory cytokines and accumulate in the spleen. MDSCs promote neoplastic progression through their suppression of anti-tumourigenic cytotoxic T-cells. MDSCs are also rapidly expanded following acute insults, but in cancer as opposed to acute inflammation, MDSCs persist. It is now recognized that a vagally-mediated, anti-inflammatory reflex arc promoting acetylcholine secretion by Cd4+ (Cd44hiSelllo) T cells, is necessary for a return to homeostasis after an acute insult. Failure of this restorative neural circuit might contribute to unabated procarcinogenic inflammation, with the chronic expansion of MDSCs driving carcinogenesis. Trefoil factor 2 (Tff2) is a secreted anti-inflammatory peptide produced by both epithelial cells and a small subset of splenic T cell. In this study, we show that splenic Tff2 is induced in vagally-modulated memory T cells to suppress the expansion of MDSCs in response to chemical and carcinogenic injury. Deletion of Tff2 interrupts this anti-inflammatory neural arc and leads to expanded MDSCs and a dramatically increased incidence of colorectal cancer. Tff2 directly suppresses proliferation of myeloid progenitors, in a large part through upregulation of cell-bound Apolipoprotein E (ApoE), which has previously been shown to suppress proliferation of haematopoietic stem and progenitor cells. The predisposition to inflammation-associated cancer can be rescued through transgenic overexpression of splenic Tff2, adenoviral transfer of Tff2 expression or transplantation of Tff2-expressing haematopoietic cells. Thus, Tff2 production in memory T cells, is regulated by the vagus nerve, plays a central role in arresting procarcinogenic MDSC proliferation, and offers a novel approach to the prevention and treatment.
2016-05-30 | GSE47596 | GEO
Project description:Immunosenescence: Immunity in the Young and Aged
| PRJNA258303 | ENA
Project description:Immunosenescence: Immunity in the Young and Aged
| PRJNA258304 | ENA
Project description:Mature blood cells are maintained throughout life by hematopoietic stem cells (HSC). With aging, both HSC self-renewal as well as multi-lineage differentiation fidelity decline, a process determined by cell-intrinsic and –extrinsic factors. We here studied which aging-associated bone marrow (BM) alterations contribute to this process. Aged specific pathogen free (SPF) WT mice have increased systemic levels of microbial compounds compared to their young counterparts. This associates with increased steady-state IL-1a/b production by multiple BM cell populations. Aging-associated inflammatory transcriptional signatures and functional myeloid-differentiation bias in HSCs were mitigated in aged IL-1R1KO SPF and WT germ-free mice. Moreover, myeloid cells from aged mice produce more IL-1b and aged mice show higher and more durable IL-1a/b increase to lipopolysaccharide (LPS) challenges. Reducing inflammatory burden in aged mice by inhibiting IL-1 signaling or by antibiotic treatment rejuvenate HSCs functions. Collectively we define the microbiome-IL-1-IL1R1 axis as a key driver of HSC aging.
2021-09-16 | GSE163503 | GEO
Project description:Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we used single-cell RNAseq to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice to wildtype controls. Our computational analysis of 14,646 single-cell transcriptomes reveals that MDSCs emerge through a previously unrealized aberrant neutrophil maturation trajectory in the spleen giving rise to a unique chemokine-responsive, immunosuppressive cell state that strongly differs from normal myeloid cells. We establish the first MDSC-specific gene signature and identify novel surface markers for improved detection and enrichment of MDSCs in murine and human samples. Our study provides a single-cell transcriptional map defining the development of MDSCs, which will ultimately enable us to specifically target these cells in cancer patients.
2019-10-21 | GSE139125 | GEO
Project description:Myeloid derived suppressor cells (MDSCs) are an immunosuppressive population of immature myeloid cells found in advanced stage cancer patients and mouse tumor models. We have identified Cd38 gene as potentially playing an essential role in MDSC biology. To determine the diffences between CD38high and CD38 low MDSCs from tumor-bearing mice, we have conducted this microarray. In this dataset, we include the expression data obtained from sorted splenic CD38high CD11b+Gr1+ cells from tumor-bearing L2-Cre;p120f/f mice, compared to CD38low CD11b+Gr1+ cells from the same mice. Using these data, we have detected differential expression of 498 genes . The Nos2 gene was among the genes most upregulated in CD38high MDSCs. 8 total samples were analyzed: 3 pairs of CD38high and CD38 low MDSCs (coming from individual mice), as well a pair of CD38high and CD38low pulled MSDCs (splenocytes from 3 mice were pulled together for sorting to increase yields). Gene expression difference was determined by univariate test (two-sample t-test) with multivariate permutation test (10,000 random permutations). A cut-off p-value of less than 0.001 and minimum 2-fold expression change were used to identify genes with significant expression differences between the two groups.
2015-08-31 | E-GEOD-71705 | biostudies-arrayexpress
Project description:Myeloid derived suppressor cells (MDSCs) are an immunosuppressive population of immature myeloid cells found in advanced stage cancer patients and mouse tumor models. To identify potential genes playing essential role in MDSC biology, we have conducted microarray analysis of gene expression in MDSCs from esophageal tumor-bearing mice, compared to immature myeloid cells from healthy littermate control mice. In this dataset, we include the expression data obtained from sorted splenic CD11b+Gr1+ cells from tumor-bearing L2-Cre;p120f/f mice, compared to healthy littermate controls. Using these data, we have identified 964 genes showing differential expression between the two groups. Among these was the Cd38 gene, which was among the genes most upregulated in MDSCs from tumor-bearing mice. 9 total samples were analyzed: 6 sample from experimental tumor-bearing mice and three pooled samples from control mice. Gene expression difference was determined by univariate test (two-sample t-test) with multivariate permutation test (10,000 random permutations). A cut-off p-value of less than 0.001 and minimum 2-fold expression change were used to identify genes with significant expression differences between the two groups.
2015-08-31 | E-GEOD-71706 | biostudies-arrayexpress