Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1176023 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to human youthful PF4 signaling, highlighting its potential in rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
2025-05-31 | GSE280042 | GEO
Project description:Platelet factors regulate wound healing and also signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here, we show that systemic platelet factor 4 (PF4) modulates cognition and its molecular signature. Klotho, a longevity and cognition-enhancing protein, acutely activated platelets and increased circulating platelet factors, most robustly platelet factor 4 (PF4). To directly test PF4 effects on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In aging mice, PF4 restored cognitive deficits and rejuvenated a molecular signature of cognition in the aging hippocampus. Augmenting platelet factors such as PF4, a possible messenger of klotho, may enhance cognition in the young brain and rejuvenate cognitive deficits in the aging brain.
2023-06-24 | GSE171929 | GEO
Project description:We show that platelet factors transfer rejuvenating effects of young plasma to the aging brain. Proteomic analysis of plasma from young and aged mice identified age-related changes in platelets. Systemic exposure of aged animals to the platelet fraction of young plasma decreased hippocampal neuroinflammation at a transcriptional and cellular level and ameliorated cognitive impairments. We identified the platelet-derived chemokine CXCL4/Platelet Factor-4 (PF4) as a pro-youthful circulating factor. Systemic PF4 administration decreased age-related neuroinflammation, restored the aging peripheral immune system to a more youthful state, and improved hippocampal-dependent learning and memory in aged mice.
2023-06-20 | GSE173254 | GEO
Project description:We discovered that platelets become activated by platelet factor 4 and have looked into how this is the case. We used phosphoproteomics to identify proteins that were phosphorylated in a band on a Western blot at 95 kDa and identified phospho STAT5. We have subsequently shown that PF4 activates platelets through the JAK/STAT pathway.
2024-06-16 | PXD043558 | Pride
Project description:Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms(1). Platelet factor 4 (PF4) is a platelets-secreted chemokine that can be activated by physical exercise. Recent studies showed that PF4 could improve cognition in aged mice(2), though whether it influences other neurological functions is vague. Here we investigated the role of PF4 in PD and normal aging mice. Intravenous administration of exogenous PF4 ameliorated both motor and non-motor symptoms of MPTP-induced PD mice, accompanying with reduced loss of nigrostriatal dopaminergic neurons and attenuated neuroinflammation in these regions. RNA sequencing showed that pathways related to inflammation were suppressed by PF4, which were confirmed by qPCR and immunohistochemical analysis. More interestingly, PF4 can also ameliorate the motor and non-motor symptoms after the loss of nigrostriatal dopaminergic neurons, and the efficacy can last for 3 weeks after PF4 administration. In addition, an improvement of motor performance and mood by PF4 was also observed in aged but not young mice. Collectively, our results show the potential of PF4 that not only be a therapeutic candidate for PD patients, but also be an option for aged people to improve their neurological performance.
2024-10-28 | GSE280106 | GEO
Project description:Srf is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. In order to test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F (KO) mice are born with normal mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased numbers and percentages of CD41+ megakaryocytes (WT: 0.41+/-0.06%; KO: 1.92+/-0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by both FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are downregulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production, due at least in part, to regulation of cytoskeletal genes. C-kit+CD41+ megakaryocyte progenitors from PF4-Cre/SRF C57BL/6 SRF WT (3) and C57BL/6 SRF KO (3) mice were sorted by flow cytometry and cultured for three days in thrombopoietin.
2010-07-13 | E-GEOD-21859 | biostudies-arrayexpress
Project description:Platelet factor 4 (PF4) is induced by klotho and rejuvenates cognition and its molecular signature in the aging hippocampus
| PRJNA721412 | ENA
Project description:Aging involves morphological and functional changes across different organs, but how these changes are linked among the different organs remains to be elucidated. Here, we uncover a central role of platelets in sys temic aging. In aged mice, the levels of platelet secreted pro inflammatory factors (PSPF) increased greatly in the serum and platelets, leading to a diffuse increase of platelet infiltration in brain, liver, lung, kidney, and aortic root. The RNA binding protein HuR/ELAVL1, a major regulator of R NA metabolism, promoted the production of PSPF in platelets. Platelet specific deletion of HuR reduced the expression of PSPF in platelets, alleviated platelet infiltration in brain, liver, lung, kidney, and aortic root, and delayed systemic aging. Our findings highlight a role of platelets in coordinating aging traits across organs.
2024-11-16 | GSE281572 | GEO
Project description:Here we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is unique to aging. We used single cell RNA sequencing (scRNA-seq) to analyze age specific platelet pathway at the clonal level.
2024-05-21 | GSE255019 | GEO
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs). However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. In this work, we demonstrate that selective depletion of arginase I (Arg1)-expressing tumor associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secrete platelet factor 4 (PF4) that reinforces interferon-γ (IFN-γ)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy.
2024-11-07 | GSE252052 | GEO