Bulk ATAC-seq of young HSCs and Selp high vs Selp low HSCs in pre-aged mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE319303 | GEO | 2026/07/06
REPOSITORIES: GEO
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Project description:Hematopoietic stem cells (HSCs) undergo functional and molecular alterations during aging that impair regenerative capacity and bias lineage output. P-selectin (Selp/CD62P) expression has been associated with inflammatory and stress-responsive hematopoietic states, but its transcriptional impact within the HSC compartment during early aging remains incompletely defined. In this study, we performed bulk RNA sequencing of phenotypically defined HSCs isolated from young mice and from pre-aged mice in which HSCs were further stratified based on Selp surface expression (Selp_high and Selp_low). Comparative transcriptomic analysis was conducted to identify gene expression programs associated with early aging and Selp-associated heterogeneity within the HSC pool. These data provide a resource for understanding molecular pathways linked to HSC functional decline and inflammatory priming during the initial stages of hematopoietic aging.
2026-07-06 | GSE319049 | GEO
Project description:During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration, impaired lymphoid cell production and ineffective erythropoiesis. In this study, we uncovered that during aging the cell surface presentation of the type-1 transmembrane protein P-selectin (CD62P, encoded by Selp) increases in a large fraction of HSCs. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with high abundance of P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation upon regenerative stress. Overexpression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and repress erythropoiesis. Moreover, IL-1β, which is chronically elevated in the aged bone marrow, triggered Selp expression in HSCs. The aged transcriptome, including Selp, was largely restored when aged HSCs were transplanted to young mice. Mechanistically, we uncovered that appropriate stimulation of P-selectin by its primary ligand, P-selectin glycoprotein ligand-1 (PSGL-1), suppressed aging-associated gene expression and reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a novel functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.
2025-03-21 | GSE269360 | GEO
Project description:Aged hematopoietic stem cells (HSCs) display myeloid-biased differentiation and reduced regenerative potential. In this study, we uncover that P-selectin (Selp) marks a subset of aged HSCs with reduced repopulation capacity. This population of HSCs expresses a prominent aging transcriptome. Overexpression of Selp in young HSCs impaired long-term reconstitution potential and repressed erythropoiesis. We show that IL-1β is elevated in aged bone marrow and administration of IL-1β induces expression of Selp and other aging-associated genes in HSCs. Finally, we demonstrate that transplantation of aged HSCs into young recipients restores a young-like transcriptome, specifically by repressing pro-inflammatory pathways, highlighting the important role of the bone marrow microenvironment in HSC aging.
2023-01-02 | GSE194273 | GEO
Project description:Increasing evidence links metabolic activity and cell growth to decline in hematopoietic stem cell (HSC) function during aging. The Lin28b/Hmga2 pathway controls tissue development and in the hematopoietic system the postnatal downregulation of this pathway causes a decrease in self renewal of adult HSCs compared to fetal HSCs. Igf2bp2 is an RNA binding protein and a mediator of the Lin28b/Hmga2 pathway, which regulates metabolism and growth signaling by influencing RNA stability and translation of its target genes. It is currently unknown whether Lin28/Hmga2/Igf2bp2 signaling impacts on aging-associated impairments in HSC function and hematopoiesis. Here, we analyzed homozygous Igf2bp2 germline knockout mice and wildtype control animals to address this question. The study shows that Igf2bp2 deletion rescues aging phenotypes of the hematopoietic system, such as the expansion of HSC numbers in bone marrow and the biased increase of myeloid cells in peripheral blood. This rescue of hematopoietic aging coincides with reduced mitochondrial metabolism and glycolysis in Igf2bp2-/- HSCs compared to Igf2bp2+/+ HSCs. Conversely, Igf2bp2 overexpression activates protein synthesis pathways in HSCs and leads to a rapid loss of self renewal by enhancing myeloid skewed differentiation in an mTOR/PI3K-dependent manner. Together, these results show that Igf2bp2 regulates energy metabolism and growth signaling in HSCs and that the activity of this pathways influences self renewal, differentiation, and aging of HSCs.
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Project description:Age-related functional decline of hematopoietic stem cells (HSC) contributes to the decline of the hematopoietic system. Growth Arrest and DNA Damage-inducible proteins (Gadd45a, Gadd45b, and Gadd45g) are robustly expressed early in HSC activation and are known to be important for DNA damage response. Gadd45b has also been shown to promote removal of 5-methylcytosine at specific loci. Given that both DNA methylation (DNAm) alterations and DNA damage have been associated with HSC aging, we sought to examine the role of Gadd45b in HSCs. To examine if Gadd45b is critical for regulating DNAm in HSCs, we performed whole genome bisulfite sequence and RNA sequencing on wild-type (WT) and Gadd45b knock-out (KO) HSCs isolated from young and old mice. Global DNAm of young KO showed increased DNAm compared to young WT, and the DNAm profiles were more similar to old HSCs, from either WT and KO, than to young WT. We examined the DNAm changes common between the Gadd45b KO (YKOvsYWT) or WT aging (OWTvsYWT). 52.5% of differentially methylated cytosines (DMCs) in YKO were also seen in normal aging, and analysis of genes with promoters near these overlapping DMCs are enriched for pathways related to immune response and development processes. We compared the expression of genes with DMCs in the promoter regions, but DMCs did not strongly correspond with transcriptional alterations. To test if these overlapping DNAm changes in young KO mice primed HSCs towards aging phenotypes, we evaluated the composition of peripheral blood and bone marrow in KO, and performed functional evaluation experiments. We found no significant differences between young KO and WT HSCs suggesting these overlapping DMCs do not contribute to aging phenotypes, reducing the potential DNAm changes contributing to aging HSC phenotypes.
2026-05-15 | GSE276335 | GEO
Project description:Hematopoietic stem cell aging leads to dysfunction of hematopoietic and immune systems, which in return contribute to organismal aging and the development of aging-related diseases. Understanding the molecular mechanisms of HSC aging is critical for developing interventions to treat and prevent aging-related diseases. Here, we show that DCAF8, a substrate receptor of E3 ubiquitin ligases, is highly expressed in HSCs and undergoes a progressive decline with age. Loss of DCAF8 in mice results in aging-like phenotype in HSCs, characterized by increased number of HSCs, decreased self-renewal capacity, cellular senescence and elevated DNA damage. Mechanistically, DCAF8 mediates the degradation of DOCK11, a guanine nucleotide exchange factor for CDC42. In the absence of DCAF8, DOCK11 accumulates, leading to elevated CDC42 activity and consequential loss of polarity of HSCs. Knocking out of Dock11 mitigates the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs. This study highlights a critical role of DCAF8 in regulating HSC aging via the DOCK11-CDC42 axis and suggests potential therapeutic targets for preventing the age-related decline in HSC functions.
2025-10-04 | GSE278044 | GEO
Project description:Hematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Epigenetic alterations are one of the hallmarks of HSC aging, and profiling of DNA methylation and histone modifications has provided potential mechanisms that contribute to HSC aging. Chromatin accessibility reflects a comprehensive transcriptional network operating in cells; however, it has not yet been investigated in HSC aging. Here we performed an integrated analysis of aged HSCs on transcriptome, chromatin accessibilities, and histone modifications. Alterations in chromatin accessibility preferentially took place in HSCs with aging, the cells at the top of hematopoietic hierarchy, suggesting that the age-associated alterations in chromatin accessibility are memorized in HSCs and are inherited to downstream progenitor cells. However, most genes with differentially accessible regions (DARs) were not actively transcribed and kept poised for activation in aged HSCs. Motifs of ATF/CREB, STAT, and CNC family transcription factors were significantly enriched at DARs in aged HSCs. These transcription factors are activated in response to external stresses such as cytokine and inflammation signals and oxidative stresses, suggesting that the long-term exposure to such stress signals have changed chromatin accessibility in HSCs to augment responses by such trained HSCs to subsequent stimuli. In contrast, aged HSC-specific gene expression occurred mainly at gene loci with poised accessible regions but not DARs without accompanying drastic chromatin reorganization, suggesting that altered cell-extrinsic stimuli or signals from aged niche largely account for this process. Our findings provide key epigenetic molecular insights into HSC aging and serve as a reference for future analysis.
2020-12-05 | GSE162659 | GEO
Project description:Analysis of gene-expression alterations in primitive LT-HSCs as early as 2 days post sex steroid ablation. This study aimed to determine potential intrinsic changes occuring in the LT-HSC population associated with sex steroid ablation (SSA) at a timepoint that preceeded the earliest reported functional hematopoietic enhancements occuring at day 7 post SSA. These results are vital in providing insight into the role of LT-HSCs in initiating SSA-mediated immune regeneration. Total RNA obtained from BM-sorted LT-HSC 2 days after sex steroid ablation compared to sham sex steroid ablation controls.
2015-03-01 | E-GEOD-64841 | biostudies-arrayexpress
Project description:Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems (UPS) are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitin-conjugating enzyme likely involved in clonal selection of HSCs, was elevated in aged murine and human HSCs. We hypothesized that the elevated levels of Ube2g1 causally contribute to aging of the hematopoietic system. Elevated levels of Ube2g1 in young HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naive T cell subpopulations, known hallmarks of aging in hematopoiesis. Interestingly, the ubiquitination function of Ube2g1 did not primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired T cell development and reduced function of HSCs. Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and the level of phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.
2025-07-10 | MSV000098473 | MassIVE
Project description:Recent years have seen exploration into the hematopoietic stem cell (HSC) niche in adult bone marrow (BM). Due to their relatively rare occurrence, research on splenic HSCs and their role in hematopoiesis under steady-state conditions has been limited. However, studies have been taken up to understand extramedullary hematopoiesis (EMH) in spleen under stress and pathological conditions. Moreover, activation of EMH also has been linked to mobilized BM derived HSCs, and contribution from the splenic HSCs has not been clear. Our studies have identified a myofibroblastic niche in spleen that supports HSCs under homeostatic conditions. To assess the maintenance and regulation of HSCs in spleen tissue by niche cells, we performed label-free mass spectrometry (MS) based quantitative proteomic analysis. The splenic HSC niche cells including capsular and trabecular myofibroblasts (or CTMs/TBs), Lin-CD45- stromal cell population (or STs) and HSPCs (Lin-CD45+c-kit+Sca-1+) were isolated by fluorescence-activated cell sorting (FACS). The sorted cells were then lysed in lysis buffer, sonicated, thermally denatured, reduced, alkylated and tryptic digests were processed, desalted and analyzed on nano-LC coupled with high resolution mass spectrometer. Using Proteome Discoverer program and computational analysis performed on the global protein expression we examined the protein-protein interactions, cell-cell interactions and molecular pathways enriched in each cell population. This study demonstrates the molecular components HSC niche and presents a model to uncover novel hematopoietic regulators crucial for improving the function of adult and pluripotent stem cell derived HSCs.
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