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Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

ABSTRACT: The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. It is unknown whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche. To address this, we compared perinatal with adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited an enrichment in genes mediating m6A mRNA methylation regulation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was rescued by deletion of Klf2, a target of m6A. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche or hematopoiesis. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE217055 | GEO | 2024/04/23

REPOSITORIES: GEO

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Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

Project description:The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. It is unknown whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche. To address this, we compared perinatal with adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited an enrichment in genes mediating m6A mRNA methylation regulation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was rescued by deletion of Klf2, a target of m6A. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche or hematopoiesis. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.

2024-04-23 | GSE217056 | GEO

Differentially expressed genes in hematopoietic stem cells after loss of Mettl3

Project description:Hematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation according to physiological demands, but how different facets of these functions are precisely regulated is not fully understood. N6-methyladenosine (m6A) mRNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deleting the m6A methyltransferase, Mettl3, from the adult hematopoietic system led to an accumulation of HSCs in the bone marrow and marked reduction of HSC reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not have any discernable impact on myeloid cell number or function. m6A sequencing on purified HSCs revealed 2,073 genes with significant m6A modification. In particular, Myc, a key regulator of HSC differentiation, was identified as a direct target of m6A in HSCs. Mettl3-deficient HSCs failed to up-regulate Myc expression upon stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results thus revealed a key role of m6A in governing HSC differentiation by regulating Myc expression. This data includes RNA-Seq analysis to showing only minor gene expression changes in adult bone marrow murine hematopoietic stem cells 10 days after Mettl3 deletion by pIpC administration compared to pIpC treated controls.

2019-03-31 | GSE123526 | GEO

The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem-cell-niche function

Project description:Mesenchymal stem cells (MSCs) And osteolineage cells contribute to the hematopoietic stem cell (HSC) Niche in the bone marrow of long bones. However, Their developmental relationships remain unclear. Here we demonstrate that different MSC populations in the developing marrow of long bones have distinct functions. Proliferative mesoderm-derived nestin- MSCs participate in fetal skeletogenesis, And lose MSC activity soon after birth. In contrast, Quiescent neural-crest-derived nestin+ Cells in the same bones preserve MSC activity, But do not generate fetal chondrocytes. Instead, They differentiate into HSC-niche-forming MSCs, Helping to establish the HSC niche by secreting Cxcl12. Perineural migration of these cells to the bone marrow requires the ErbB3 receptor. The neonatal Nestin-GFP+ PDGFR- Cell population also contains Schwann-cell precursors, But does not comprise mature Schwann cells. Thus, In the developing bone marrow HSC-niche-forming MSCs share a common origin with sympathetic peripheral neurons and glial cells, And ontogenically distinct MSCs have non-overlapping functions in endochondrogenesis and HSC niche formation. Total RNA was isolated from small numbers of FACS sorted stromal cells, obtained from neonatal Nes-Gfp bone marrow preparations (2 biological replicates). Each independent set of samples was obtained from pooled skeletal elements (long bones and sterna) form multiple littermates.

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DARTseq identifies m6A targets in mouse primary cells

Project description:The goal of this study is to identify m6A targets in mouse HSC and MPP1-4 cells Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. When exposed to stress such as inflammation, stem cells can rapidly undergo symmetric commitment divisions to generate differentiated progenitors for tissue regeneration and immune maintenance. m6A RNA methylation controls symmetric commitment and inflammation of hematopoietic stem cells (HSCs) through unknown mechanisms. Here, we demonstrate that the nuclear speckle protein SON is an essential m6A target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of m6A identified that m6A mRNA methylation of Son increases during HSC commitment. Upon m6A depletion, Son mRNA increases, but its protein is depleted. Reintroduction of SON rescues defects in HSC symmetric commitment divisions and engraftment. Conversely, Son deletion results in a loss of HSC fitness, while overexpression of SON improves mouse and human HSC engraftment potential by increasing quiescence. Additionally, SON nuclear speckles asymmetrically and symmetrically segregate during HSC division, correlating with hematopoietic differentiation. Mechanistically, we found that SON rescues MYC and suppresses the METTL3-HSC inflammatory gene expression program by indirectly reducing double-stranded RNAs and directly suppressing nascent transcription of proinflammatory chemokine CCL5. Depletion of CCL5 partially rescues the functional defect of m6A-deficient HSCs. Thus, our findings define a m6A-SON-CCL5 axis that controls inflammation and HSC fate.

2023-12-07 | GSE231862 | GEO

m6A RNA modification controls cell fate transition in mammalian embryonic stem cells (RNA methylation)

Project description:Here we determine the map of RNA methylation (m6A) in mouse embrionic stem cells, and Mettl3 knock out cells Examination of m6A modification sites on the transcriptome of mouse Embryonic stem cells and Embryonic Mettl3 knock out cells, using a m6A specific antibody.

2014-10-16 | E-GEOD-52662 | biostudies-arrayexpress

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

The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem-cell-niche function

2014-10-15 | GSE61695 | GEO

Hematopoietic-mesenchymal signal regulates properties of mesenchymal stem cells

Project description:It is well known that the properties of hematopoietic stem cells (HSCs) such as their ability to self-renew, and multipotency are maintained through interactions with mesenchymal cells. Meanwhile, the identification of cells that are the key component of niche remains a subject of dispute. Mesenchymal stem cells (MSCs) are one of the niche component cells, MSCs are one of the niche component cells which provide stemness signal to HSCs, while it is also hypothesized that there is also a counterpart signal from hematopoiesistic cells to mesenchymeal cells, as HSCs also constitute core stem cells niche for MSCs. Although mesenchymal stem cells (MSCs) have also been studied intensively, the signals involved in the maintenance of their properties have not attracted much attentions. We used microarrays to detail the global programme of gene expression underlying HSC-MSC interaction and identified distinct classes of regulated genes during this process.

2021-12-31 | GSE186250 | GEO

Mettl3-dependent m6A targets in adult murine hematopoietic stem cells

Project description:Hematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation according to physiological demands, but how different facets of these functions are precisely regulated is not fully understood. N6-methyladenosine (m6A) mRNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deleting the m6A methyltransferase, Mettl3, from the adult hematopoietic system led to an accumulation of HSCs in the bone marrow and marked reduction of HSC reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not have any discernable impact on myeloid cell number or function. m6A sequencing on purified HSCs revealed 2,073 genes with significant m6A modification. In particular, Myc, a key regulator of HSC differentiation, was identified as a direct target of m6A in HSCs. Mettl3-deficient HSCs failed to up-regulate Myc expression upon stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results thus revealed a key role of m6A in governing HSC differentiation by regulating Myc expression. This data includes m6A sequencing data on HSCs from wild-type or Mettl3-deficient mice, revealing the Mettl3-depedent m6A targets in HSCs.

2019-03-31 | GSE123525 | GEO

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