Sex-dependent niche responses modulate steady-state and regenerative hematopoiesis
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ABSTRACT:
PROVIDER: PRJNA1063675 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27503801_1.fastq.gz | Fastqsanger.gz | |||
| SRR27503801_2.fastq.gz | Fastqsanger.gz | |||
| SRR27503802_1.fastq.gz | Fastqsanger.gz | |||
| SRR27503802_2.fastq.gz | Fastqsanger.gz | |||
| SRR27503803_1.fastq.gz | Fastqsanger.gz |
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Project description:Hematopoietic stem cells (HSCs) adapt to organismal blood production needs. While it has been established that sexual dimorphism drives differential hematopoietic function in males vs. females, the mediators responsible for these effects remain unclear. Here, we characterize hematopoiesis in male and female mice at steady state and during regeneration following hematopoietic stem cell transplantation (HST). We found that steady-state males possessed greater bone marrow (BM) hematopoietic stem and progenitor cell (HSPC) populations and varied in frequency for stromal populations. PCR analysis from stromal CD45(-)-purified BM cells demonstrated alterations in niche genes, including Ptn, IL6, Angpt1, Vcam1, and Spp1, together suggesting the male microenvironment is primed for HSC differentiation and mobilization. RNA sequencing of BM lineage(-) cells revealed differential expression of genes, like Hif1a and Aldh1, and corresponding cellular pathways—including those involving reactive oxygen species, oxidative phosphorylation, and Tnf-a signaling via NF-κB—underscoring male lineage(-) cells as more inflammatory and proliferative. To determine the functional outcomes of steady-state transcriptional differences we performed sex-matched and mismatched transplantation studies of lineage(-) donor cells into male and female recipients. We demonstrated a role for TNF-a-driven proliferation of male donor cells and Cxcl12-mediated homing into male recipients during short-term 56-day HST recovery. Serial transplantation of lineage(-) cells suggested the male short-term proliferative advantage may precede long-term disadvantages of inflammation-induced exhaustion. We show that sex-specific cellular and molecular signaling, marked by differing expression of niche factors and inflammatory mediators, shapes normal and regenerative hematopoiesis, with implications for the fundamental and clinical understanding of hematopoietic function.
2025-01-01 | GSE253024 | GEO
Project description:Adult hematopoietic stem cells (HSCs) reside primarily in bone marrow. However, hematopoietic stresses such as myelofibrosis, anemia, pregnancy, infection or myeloablation can mobilize HSCs to the spleen and induce extramedullary hematopoiesis (EMH). While the bone marrow HSC niche has been studied intensively, the EMH niche has received little attention. Here, we systematically assessed the physiological sources of the key niche factors, SCF and CXCL12, in the mouse spleen after EMH induction by cyclophosphamide plus granulocyte colony-stimulating factor, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21+ stromal cells, primarily around sinusoids in red pulp, while Cxcl12 was expressed by a subset of Tcf21+ stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21+ stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells or Scf or Cxcl12 from Tcf21+ stromal cells severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow hematopoiesis. Endothelial cells and Tcf21+ stromal cells thus create the splenic EMH niche, which is necessary for the physiological response to diverse hematopoietic stresses. Unfractionated spleen cells (2 replicates) and FACS-sorted VE-cadherein negative Scf-GFP positive cells (3 replicates)
2015-08-01 | E-GEOD-71288 | biostudies-arrayexpress
Project description:Transcriptional Activation of Regenerative Haematopoiesis via Niche Sensing
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Project description:Adult hematopoietic stem cells (HSCs) reside primarily in bone marrow. However, hematopoietic stresses such as myelofibrosis, anemia, pregnancy, infection or myeloablation can mobilize HSCs to the spleen and induce extramedullary hematopoiesis (EMH). While the bone marrow HSC niche has been studied intensively, the EMH niche has received little attention. Here, we systematically assessed the physiological sources of the key niche factors, SCF and CXCL12, in the mouse spleen after EMH induction by cyclophosphamide plus granulocyte colony-stimulating factor, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21+ stromal cells, primarily around sinusoids in red pulp, while Cxcl12 was expressed by a subset of Tcf21+ stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21+ stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells or Scf or Cxcl12 from Tcf21+ stromal cells severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow hematopoiesis. Endothelial cells and Tcf21+ stromal cells thus create the splenic EMH niche, which is necessary for the physiological response to diverse hematopoietic stresses.
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Project description:The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. This antecedent angiogenesis meets the nutrient requirements for subsequent rapid axon regeneration and remyelination. Nevertheless, the mechanisms of vascular niche in the regulation of peripheral nerve remain unclear. The axon guidance molecule Netrin-1 (NTN1) is widely expressed in peripheral nerves and particularly was found up-regulated in sciatic nerve stump after peripheral nerve injury (PNI). Herein, we demonstrated that NTN1-high endothelial cells (NTN1+ECs) were the critical component of vascular niche, fostering angiogenesis, axon regeneration and repair-related phenotypes. And we also found that NTN1+ECs derived exosomes (NTN1 EC-EXO) were involved in the formation of vascular niche as a critical role. Multi-omics analysis further verified that NTN1 EC-EXO carried a low-level expression of let7a-5p and activated key pathways associated with niche formation including focal adhesion, axon guidance, PI3K-AKT signaling pathway and mTOR signaling pathway. Taken together, our findings suggested the potential construction of a pre-regenerative niche induced by NTN1 EC-EXO, thereby establishing a conductive microenvironment for nerve repair and facilitating the functional recovery after PNI in the early injury phase.
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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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Project description:Outside-in integrin signaling regulates cell fate decisions in a variety of cell types, including hematopoietic stem cells (HSCs). Our earlier published studies showed that interruption of periostin (POSTN) and integrin-αv (ITGAV) interaction induces faster proliferation in HSCs with developmental stage-dependent functional effects. In this study, we examined the role of POSTN-ITGAV axis in lymphohematopoietic activity in spleen that hosts a rare population of HSCs, the functional regulation of which is not clearly known. Vav-iCre-mediated deletion of Itgav in the hematopoietic system led to higher proliferation rates, resulting in increased frequency of primitive HSCs in the adult spleen. However, in vitro CFU-C assays demonstrated a poorer differentiation potential following Itgav deletion. This also led to a decrease in the white pulp area with a significant decline in the B cell numbers. Systemic deletion of its ligand, POSTN, phenocopied the effects noted in Vav-Itgav-/- mice. Histological examination of Postn-deficient spleen also showed an increase in the spleen trabecular areas. Importantly, these are the myofibroblasts of the trabecular and capsular areas that expressed high levels of POSTN within the spleen tissue. In addition, vascular smooth muscle cells also expressed POSTN. Through CFU-S12 assays, we showed that hematopoietic support potential of stroma in Postn-deficient splenic hematopoietic niche was defective. Overall, we demonstrate that POSTN-ITGAV interaction plays an important role in spleen lymphohematopoiesis.
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