Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bap1 shapes the bone marrow niche for lymphopoiesis by fine-tuning epigenetic profiles in endosteal mesenchymal stromal cells [ChIP-Seq]

ABSTRACT: Hematopoiesis occurs within a unique bone marrow (BM) microenvironment which consists of various niche cells, cytokines, growth factors and extracellular matrix components. These multiple components directly or indirectly regulate the maintenance and differentiation of hematopoietic stem cells (HSCs). Here we report that Bap1 in BM mesenchymal stromal cells (MSCs) is critical for the maintenance of HSCs and B lymphopoiesis. Mice lacking Bap1 in MSCs show aberrant differentiation of hematopoietic stem and progenitor cells, impaired B lymphoid differentiation, and expansion of myeloid lineages. Mechanistically, Bap1 loss in distinct endosteal MSCs, expressing Prx1 but not Lepr, leads to aberrant expression of genes affiliated with BM niche functions. Bap1 deficiency leads to a reduced expression of pro-hematopoietic factors such as Scf, caused by increased H2AK119-ub1 and H3K27-me3 levels on the promoter region of these genes. On the other hand, the expression of myelopoiesis stimulating factors including Csf3 was increased by enriched H3K4-me3 and H3K27-ac levels on their promoter, causing myeloid skewing. Notably, loss of Bap1 substantially blocks B lymphopoiesis and skews the differentiation of hematopoietic precursors toward myeloid lineages in vitro, which is reversed by G-CSF neutralization. Thus, our study uncovers a key role for Bap1 expressed in endosteal MSCs in controlling normal hematopoiesis in mice by modulating expression of various niche factors governing lymphopoiesis and myelopoiesis via histone modifications.

ORGANISM(S): Mus musculus

PROVIDER: GSE198649 | GEO | 2022/04/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Bap1 shapes the bone marrow niche for lymphopoiesis by fine-tuning epigenetic profiles in endosteal mesenchymal stromal cells [RNA-Seq]

Project description:Hematopoiesis occurs within a unique bone marrow (BM) microenvironment which consists of various niche cells, cytokines, growth factors and extracellular matrix components. These multiple components directly or indirectly regulate the maintenance and differentiation of hematopoietic stem cells (HSCs). Here we report that Bap1 in BM mesenchymal stromal cells (MSCs) is critical for the maintenance of HSCs and B lymphopoiesis. Mice lacking Bap1 in MSCs show aberrant differentiation of hematopoietic stem and progenitor cells, impaired B lymphoid differentiation, and expansion of myeloid lineages. Mechanistically, Bap1 loss in distinct endosteal MSCs, expressing Prx1 but not Lepr, leads to aberrant expression of genes affiliated with BM niche functions. Bap1 deficiency leads to a reduced expression of pro-hematopoietic factors such as Scf, caused by increased H2AK119-ub1 and H3K27-me3 levels on the promoter region of these genes. On the other hand, the expression of myelopoiesis stimulating factors including Csf3 was increased by enriched H3K4-me3 and H3K27-ac levels on their promoter, causing myeloid skewing. Notably, loss of Bap1 substantially blocks B lymphopoiesis and skews the differentiation of hematopoietic precursors toward myeloid lineages in vitro, which is reversed by G-CSF neutralization. Thus, our study uncovers a key role for Bap1 expressed in endosteal MSCs in controlling normal hematopoiesis in mice by modulating expression of various niche factors governing lymphopoiesis and myelopoiesis via histone modifications.

2022-04-25 | GSE198823 | GEO

Inflammation of the Aged Bone Marrow Niche Drives Blood Aging

Project description:Hematopoietic aging is defined by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to dysfunctional blood production. Signals from the bone marrow (BM) microenvironment dynamically tailor hematopoiesis, but the effect of aging on the niche and the contribution of the aging niche to blood aging still remains unclear. Here, we show the development of an inflammatory milieu in the aged marrow cavity, which drives both niche and hematopoietic system remodeling. We find decreased numbers and functionality of osteogenic endosteal mesenchymal stromal cells (MSC), expansion of pro-inflammatory perisinusoidal MSCs, and deterioration of the central marrow sinusoidal endothelium, which together create a self-reinforcing inflamed BM milieu. Single cell molecular mapping of old niche cells further confirms disruption of cell identities and enrichment of inflammatory response genes. Inflammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation at the expense of lymphoid and erythroid commitment, and hinders hematopoietic regeneration. Remarkably, both defective hematopoietic regeneration, niche deterioration and HSC aging can be improved by blocking inflammatory IL-1 signaling. Our results indicate that targeting the pro-inflammatory niche milieu can be instrumental in restoring blood production during aging.

2022-11-02 | GSE168613 | GEO

Mature B cells and Mesenchymal Stem Cells control emergency myelopoiesis

Project description:Systemic inflammation halts lymphopoiesis and prioritizes myeloid cell production. How blood cell production switches from homeostasis to emergency myelopoiesis is incompletely understood. Here we show that Lymphotoxin-b receptor (LTbR) signaling in combination with TNF and IL1 receptor signaling in mesenchymal stem cells (MSCs) downregulates Il7 expression to shutdown lymphopoiesis during systemic inflammation. LTbR signaling in MSCs also promoted CCL2 production to enable inflammatory monocyte egress from the bone marrow. Furthermore, pharmacological or genetic blocking of Il7 downregulation in MSCs impaired myeloid cell production and egress, which reduced survival against systemic bacterial and viral infections. Interestingly, lymphotoxin a1b2 delivered by B-lineage cells, and specifically by mature B cells, contributed to promote Il7 downregulation and reduce MSC lymphopoietic activity. Our studies revealed an unexpected role for LTbR signaling in MSCs and identified mature B cells as an important regulator of emergency myelopoiesis.

2023-01-20 | GSE218505 | GEO

PDGFB-expressing MSCs improve human hematopoietic stem cell engraftment in immunodeficient mice

Project description:The bone marrow (BM) niche regulates multiple HSC processes. Clinical treatment for hematological malignancies, by HSC transplantation often requires preconditioning total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies to enhance HSC regeneration in irradiated BM are needed. We compared the effects of niche factors EGF, FGF2 and PDGFB on HSC hematopoietic regeneration using human MSCs that were transduced with these factors via lentiviral vectors. Among above niche factors tested, PDGFB-MSCs most significantly improved human hematopoietic cell engraftment in immunodeficient mice. PDGFB-MSC-treated BM more efficiently enhanced transplanted human HSC self-renewal in secondary transplantations from primary recipients. Although PDGFB-MSCs did not directly increase HSC expansion in vitro, GSEA revealed anti-apoptotic signaling being increased in PDGFB-MSCs versus GFP-MSCs. PDGFB-MSCs had enhanced survival and expansion after transplantation, leading to an enlarged humanized niche cell pool. Our study demonstrates the efficacy of MSC-mediated niche factors in clinical HSC transplantation for patients.

2020-06-22 | GSE113857 | GEO

Myeloid Skewing in Aging Bone Marrow Depends on Long-lived Plasma Cell Accumulation

Project description:Aging results in a reduction in B lymphopoiesis and an increase in myelopoiesis in mice and humans. We investigated how cellular changes in the aging hematopoietic microenvironment contribute to these alterations in hematopoiesis and found that long-lived plasma cells (LLPCs) increase in number in the bone marrow of old mice. The LLPCs exhibited a Toll Like Receptor activation signal, and their accumulation was partially dependent on inflammatory cytokines. LLPCs were able to stimulate myelopoiesis from hematopoietic stem cells and myeloid progenitors in vitro, and anti-CD138 antibody-mediated depletion of LLPCs or blockade of pro-inflammatory signaling in old mice in vivo resulted in a significant reduction in LLPC number and attenuated myeloid development. However, B lymphopoiesis remained suppressed. These data identify the increase in LLPC number as obligate for age-associated increases in myelopoiesis and provide evidence that, in the context of aging, enhanced myelopoiesis and depressed lymphopoiesis are distinct, independently regulated processes.

2019-07-16 | GSE112939 | GEO

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [5]

Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs and BMECs following conditional deletion of NTN1 within BMECs or MSCs to characterize transcriptional alterations within BM niche cells resulting from a deficiency of niche derived NTN1.

2023-04-14 | GSE227147 | GEO

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [1]

2023-04-14 | GSE227143 | GEO

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [2]

Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs derived from young (3 month old) and aged (18 month old) mice to characterize transcriptional alterations within BM MSCs during aging.

2023-04-14 | GSE227144 | GEO

mRAN expression profiles in bone marrow mesenchymal stem cells (MSC) from Wild Type and Lama4-deficient mice co-cultured with MLL-AF9 AML cells

Project description:Bone marrow (BM) niche contributes to hematopoietic regeneration and can be remodeled by leukemic cells. We have found that Lama4 deletion in mouse mesenchymal stem cells (MSCs) could promote the proliferation of MLL-AF9 acute myeloid leukemia (AML) cells and chemoresistance of the cells to chemotherapy cytarabine. However, whether Lama4 deficient MSCs are more susseptible for AML cell remodeling remains to be explored. Here we report that differential molecular alterations in Lama4 deficient MSCs compared to wild type MSCs after being exposed to the AML cells for 48hours, which might be related to the enhanced AML cell proliferation and chemoresistance.

2022-02-16 | GSE185846 | GEO

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [3]

Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BMECs derived from young (3 month old) and aged (18 month old) mice to characterize transcriptional alterations within BMECs during aging.

2023-04-14 | GSE227145 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data