Differentially regulated genes in normal LT-HSC vs ST-HSC
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE9189 | GEO | 2008/05/07
SECONDARY ACCESSION(S): PRJNA105245
REPOSITORIES: GEO
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Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. Experiment Overall Design: LT-HSC (Lin-cKit+Sca1+CD34-CD135-) and ST-HSC (Lin-cKit+Sca1+CD34+CD135-) cells were prospectively sorted from the BM of MxCre-.Pbx1f/f control mice harvested 4 weeks after the last injection of poly(I:C).
2008-06-20 | E-GEOD-9189 | biostudies-arrayexpress
Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes are associated with the Tgf-b pathway, which serves a major role in maintaining HSC quiescence. Pbx1-deficient LT-HSCs are unable to up-regulate the cyclin dependent kinase inhibitor p57 in response to Tgf-b, providing a mechanism through which Pbx1 maintenance of stem cell self-renewal is achieved. Keywords: genetic modification
2008-05-07 | GSE9188 | GEO
Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes are associated with the Tgf-b pathway, which serves a major role in maintaining HSC quiescence. Pbx1-deficient LT-HSCs are unable to up-regulate the cyclin dependent kinase inhibitor p57 in response to Tgf-b, providing a mechanism through which Pbx1 maintenance of stem cell self-renewal is achieved. Experiment Overall Design: Highly efficient Pbx1 deletion was induced with poly(I:C) in 3 young MxCre+.Pbx1f/f mutant or 2 MxCre-.Pbx1f/f control mice. LT-HSC (Lin-cKit+Sca1+CD34-CD135-) cells were prospectively sorted from bone marrow of individual mice harvested 4 weeks after the last injection of poly(I:C).
2008-06-20 | E-GEOD-9188 | biostudies-arrayexpress
Project description:The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration and apoptosis, but the interaction between intracellular Ca2+ and cytoplasmic chaperon protein in regulating fate options of long term-HSCs (LT-HSC) is unknown. We created a S100A6 conditional knockout mouse model in the hematopoietic system and our studies showed that in S100A6KO, the number of LT-HSCs was significantly reduced and HSCs engrafted poorly. After 5FU challenge, the frequency of S100A6KO HSCs remained significantly low. Our data showed that S100A6 failed to self-renew through Akt pathway in an intracellular calcium (Cai2+)-dependent manner. Expression profiling of S100A6KO obtained from gene signatures revealed that cytosolic calcium level and proteins translocation to mitochondria were decreased. Mitochondrial oxidative phosphorylation was impaired in S100A6KO. Proteomic data indicated Hsp90 protein and chaperonin family were reduced. Our findings demonstrated that S100A6 regulates fate options of HSCs self-renewal through integrating Akt signaling, specifically governing mitochondria metabolic function and protein quality.
2020-06-22 | PXD015854 | Pride
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2020-02-08 | GSE144933 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2021-01-12 | GSE164609 | GEO
Project description:All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.
2019-10-03 | GSE138298 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2020-02-08 | GSE144934 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2020-07-01 | GSE151333 | GEO
Project description:we investigate the role of YTHDC1 in normal hematopoiesis and adult hematopoietic stem/progenitor cell (HSPC) maintenance in vivo. Utilizing conditional Ythdc1 knockout mice ,we show that YTHDC1 is required for hematopoietic stem cell (HSC) maintenance as well as self-renewal of HSC. Transcriptome analysis identified many differentially expressed genes (DEGs) between WT and YTHDC1-KO LT-HSCs.
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