MLL-Associated Leukemias Drive Expression of MiR-9, Required for Tumorigenesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 525-525
Author(s):  
Colles Price ◽  
Ping Chen ◽  
Zejuan Li ◽  
Yuanyuan Li ◽  
Anissa Wiley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
The United States ◽  
Cellular Migration

Abstract Abstract 525 Acute leukemia represents one of the most deadly cancers in the United States. Clinical treatments in leukemia have progressed significantly through the use of therapies targeted specifically to chromosomal translocations. The success of these therapies has provided a model for future treatment in various cancers. However, there are various subtypes of leukemia where five-year survival and relapse rates have poor clinical outcome, indicating that new therapies are needed. A particular leukemia subtype, namely mixed lineage leukemia (MLL)-rearranged leukemia that is a result of chromosomal rearrangements leading to fusions between MLL and partner genes, is associated with a dismal outcome. Therapeutic targeting of MLL rearrangements has proven challenging as there have been dozens of described rearrangements. An emerging hallmark of cancer is the deregulation of non-coding RNAs called microRNAs (miRs). We hypothesized that MLL-associated leukemias have aberrant microRNA expression. We performed microRNA microarray analyses on leukemia patient samples and showed that microRNA-9 (miR-9) is highly upregulated in MLL-associated leukemias. We discovered that expression of miR-9 enhances cell transformation in vitro and tumorigenesis in vivo, and the opposite is true when miR-9 function is inhibited by anti-miR sponges. Interestingly, we observed that mice transplanted with both MLL-AF9 and miR-9 had a significantly higher amount of blast-like cells and immature cells in the bone marrow and fewer in the peripheral blood compared to mice transplanted with MLL-AF9 alone. Furthermore, inhibition of miR-9 function causes a significant defect in stem cell self-renewal and myeloid differentiation. Thus, this suggests that miR-9 has a critical role in stem cell potentiation and myeloid promotion in MLL-associated leukemias. To investigate target genes of miR-9, we correlated microarray expression of miR-9 and those of its putative target genes predicted with multiple prediction algorithms. We identified six potential target genes that exhibit a significantly inverse correlation of expression with miR-9 and are inhibited in MLL-associated leukemia. These identified genes are Transforming growth factor beta-induced protein (TGFBI), E-cadherin (CDH1), Nuclear factor-kappa-B p105 subunit (NFkB1), Ras homolog gene family member H (RHOH), Ring1 and YY1-binding protein (RYBP) and Foxhead Box O3 (FOXO3), We demonstrated that all these targets genes are inhibited upon expression of miR-9, in vitro and in vivo and blocking miR-9 function rescues their expression. As these target genes affect multiple cell processes such as proliferation, stem cell differentiation, chromatin remodeling, and cellular migration, it appears that miR-9 is a potential master regulator during MLL-associated tumorigenesis. Disclosures: No relevant conflicts of interest to declare.

Abstract 206: Stem Cell-derived Exosomes Induce Cardiac Repair via mRNA Modification

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Prabhu Mathiyalagan ◽  
Yaxuan Liang ◽  
Adriano S Martins ◽  
Douglas W Losordo ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Myocardial Ischemia ◽  
Target Genes ◽  
Critical Role ◽  
Cell Communication ◽  
Target Cells ◽  
Mouse Heart ◽  
Loss Of Function

Exosomes are cell-derived nanovesicles that carry and shuttle microRNAs (miRNAs) to mediate cell-cell communication. Vast majority of cell types including cardiac myocytes and progenitors actively secrete exosomes, whose miRNA contents are altered after physiological or pathological changes such as myocardial ischemia (MI). In this new study, we have discovered that chemical modification to mRNAs is a novel regulator of ischemia-induced gene expression changes in the heart. We hypothesized that the benefits of human CD34 + stem cell-derived exosomes (CD34exo) are mediated by mRNA modifications in the target cells via miRNA delivery. MiRNA profiling and bioinformatic analysis identified that CD34exo is selectively enriched with a number of miRNAs that directly target genes implicated in regulation of mRNA modifications. Interestingly, under myocardial ischemia, there was a significant increase in mRNA modifications in the mouse heart, which was decreased by about 70% with CD34exo-treatment. In line with the in vivo MI data, in vitro hypoxic stimulation in neonatal / adult rodent myocytes and non-myocytes increased mRNA modifications and controls known regulators of those mRNA modifications. Loss-of-function studies for regulators of mRNA modifications attenuated hypoxia-induced changes to epitranscriptome indicating important roles for these molecules under stress conditions. Finally, using gain-of-function and loss-of-function studies, we demonstrate that miR-126, one of the most enriched miRNAs in CD34exo, plays a critical role in regulating the mRNA modifications. We conclude that miRNAs enriched in CD34exo mediate their cardioprotective effect at least in part, by regulating the mRNA epitranscriptome of the target cell. Our new data suggests hypoxia as a novel regulator of the mRNA epitranscriptome and provides novel insights to post-transcriptional gene regulation in the heart.

Endoglin Identifies the First Wave of Hematopoietic Progenitors During Embryogenesis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1600-1600
Author(s):  
Luciene Borges ◽  
Michelina Iacovino ◽  
June Baik ◽  
Tim Mayerhofer ◽  
Michelle Letarte ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Es Cells ◽  
Critical Role ◽  
Pcr Analysis ◽  
Hematopoietic Progenitors ◽  
Double Positive ◽  
Stromal Cell Line

Abstract Abstract 1600 Endoglin (Eng), an ancillary receptor for several members of the Transforming Growth Factor (TGF)-beta superfamily, plays a critical role in early development. Eng-/- embryos dye around 10.5 dpc due primarily to vascular and cardiac abnormalities. Yolk sacs (YS) of 9.5 dpc Eng-/- embryos present abnormal vasculature and anemia. However, the mechanism by which endoglin leads to an anemic phenotype is unclear. Using in vitro differentiation of Eng-/- ES cells, we have previously demonstrated that endoglin is required for proper hemangioblast and primitive hematopoietic development. To test the hypothesis that endoglin might have a direct effect on blood formation, here we investigated the role of endoglin during hematopoiesis in vivo. We first evaluated YS from 9.5 dpc Eng-/- embryos and observed significantly reduced numbers of hematopoietic colony-forming cells (CFCs), in particular GEMMs and BFU-Es, when compared to both Eng+/− and Eng+/+ embryos. Real-time PCR analysis revealed decreased expression of embryonic globin, Gata-1, and SCL in the mutant YS. We then investigated the function of endoglin in wild-type mice by sorting the endoglin positive and negative population from E7.5 to 9.5 CD1 mouse embryos. When cultured on the stromal cell line OP9 in the presence of hematopoietic cytokines, only cell cultures derived from the Eng+ fraction gave rise to hematopoietic progenitors, as evidenced by colony assays and FACS analyses. Engneg cells did not produce any hematopoietic colonies. We then separated cells into 4 fractions using Eng and Flk-1, and found that from E7.5-9.5, the hematopoietic progenitor activity resided in the Eng+Flk-1+ double-positive fraction. FACS and microarray analyses of the 4 fractions in E7.5 embryos demonstrated that the Eng+Flk-1+ fraction highly expresses both endothelial and hematopoietic markers, including VE-Cadherin, Tie-2, PECAM1, Gata-1, SCL, and Lmo2, indicative of hemogenic endothelial potential. Taken together, our findings demonstrate that endoglin marks the first wave of hematopoietic progenitors during development, pointing to a defined role for endoglin in the specification of YS hemogenic endothelium as early as E7.5, in addition to its well defined role in vascular branching and remodeling. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Non-Ionizing Radiation for Cardiac Human Amniotic Mesenchymal Stromal Cell Commitment: A Physical Strategy in Regenerative Medicine

2018 ◽  
Vol 19 (8) ◽  
pp. 2324 ◽  
Author(s):  
Mario Ledda ◽  
Enrico D’Emilia ◽  
Maria Lolli ◽  
Rodolfo Marchese ◽  
Claudio De Lazzari ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Therapy ◽  
Adult Stem Cells ◽  
Myocardial Damage ◽  
Stem Cell Differentiation ◽  
Differentiation Markers ◽  
Innovative Strategy ◽  
Cell Commitment

Cell therapy is an innovative strategy for tissue repair, since adult stem cells could have limited regenerative ability as in the case of myocardial damage. This leads to a local contractile dysfunction due to scar formation. For these reasons, refining strategy approaches for “in vitro” stem cell commitment, preparatory to the “in vivo” stem cell differentiation, is imperative. In this work, we isolated and characterized at molecular and cellular level, human Amniotic Mesenchymal Stromal Cells (hAMSCs) and exposed them to a physical Extremely Low Frequency Electromagnetic Field (ELF-EMF) stimulus and to a chemical Nitric Oxide treatment. Physically exposed cells showed a decrease of cell proliferation and no change in metabolic activity, cell vitality and apoptotic rate. An increase in the mRNA expression of cardiac and angiogenic differentiation markers, confirmed at the translational level, was also highlighted in exposed cells. Our data, for the first time, provide evidence that physical ELF-EMF stimulus (7 Hz, 2.5 µT), similarly to the chemical treatment, is able to trigger hAMSC cardiac commitment. More importantly, we also observed that only the physical stimulus is able to induce both types of commitments contemporarily (cardiac and angiogenic), suggesting its potential use to obtain a better regenerative response in cell-therapy protocols.

scholarly journals NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

2020 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Yan He ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Xenograft Model ◽  
Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Claudia Noack ◽  
Maria P Zafiriou ◽  
Anke Renger ◽  
Hans J Schaeffer ◽  
Martin W Bergmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cellular Localization ◽  
Target Genes ◽  
Critical Role ◽  
Isolated Cells ◽  
Cardiac Progenitor Cell

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.

scholarly journals Human adipose stem cell differentiation is highly affected by cancer cells both in vitro and in vivo: implication for autologous fat grafting

2017 ◽  
Vol 8 (1) ◽  
pp. e2568-e2568 ◽  
Author(s):  
Francesca Paino ◽  
Marcella La Noce ◽  
Diego Di Nucci ◽  
Giovanni Francesco Nicoletti ◽  
Rosa Salzillo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Fat Grafting ◽  
Adipose Stem Cell ◽  
Autologous Fat Grafting ◽  
Autologous Fat ◽  
Human Adipose Stem Cell

scholarly journals Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of Glioblastoma

2020 ◽  
Author(s):  
Montserrat Lara-Velazquez ◽  
Natanael Zarco ◽  
Anna Carrano ◽  
Jordan Phillipps ◽  
Emily S Norton ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Migration ◽  
Brain Tumor ◽  
Primary Cultures ◽  
Cellular Migration ◽  
Tumor Initiating Cells ◽  
The Impact

Abstract Background Glioblastomas (GBMs) are the most common primary brains tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for reasons that remain unknown. One potential explanation is the proximity of these tumors to the cerebrospinal fluid (CSF) and its contained chemical cues that can regulate cellular migration and differentiation. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods We utilized patient-derived CSF and primary cultures of GBM brain tumor initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using TCGA database. SERPINA3 expression changes were evaluated at both the mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell behavior were evaluated by transwell assay (for cell migration), and alamar blue and Ki67 (for viability and proliferation respectively). Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results GBM CSF induced a significant increase in BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. Silencing of SERPINA3 induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 overexpression increased cell migration. In vivo, mice orthotopically-injected with SERPINA3 KD BTICs showed increased survival. Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

scholarly journals Analysis of Venezuelan Equine Encephalitis Virus Capsid Protein Function in the Inhibition of Cellular Transcription

2007 ◽  
Vol 81 (24) ◽  
pp. 13552-13565 ◽  
Author(s):  
Natalia Garmashova ◽  
Svetlana Atasheva ◽  
Wenli Kang ◽  
Scott C. Weaver ◽  
Elena Frolova ◽  
...  
Keyword(s):  
Capsid Protein ◽  
Protein Function ◽  
Sindbis Virus ◽  
New World ◽  
Critical Role ◽  
The United States ◽  
Nuclear Pore ◽  
Cellular Transcription

ABSTRACT The encephalitogenic New World alphaviruses, including Venezuelan (VEEV), eastern (EEEV), and western equine encephalitis viruses, constitute a continuing public health threat in the United States. They circulate in Central, South, and North America and have the ability to cause fatal disease in humans and in horses and other domestic animals. We recently demonstrated that these viruses have developed the ability to interfere with cellular transcription and use it as a means of downregulating a cellular antiviral response. The results of the present study suggest that the N-terminal, ∼35-amino-acid-long peptide of VEEV and EEEV capsid proteins plays the most critical role in the downregulation of cellular transcription and development of a cytopathic effect. The identified VEEV-specific peptide CVEE33-68 includes two domains with distinct functions: the α-helix domain, helix I, which is critically involved in supporting the balance between the presence of the protein in the cytoplasm and nucleus, and the downstream peptide, which might contain a functional nuclear localization signal(s). The integrity of both domains not only determines the intracellular distribution of the VEEV capsid but is also essential for direct capsid protein functioning in the inhibition of transcription. Our results suggest that the VEEV capsid protein interacts with the nuclear pore complex, and this interaction correlates with the protein's ability to cause transcriptional shutoff and, ultimately, cell death. The replacement of the N-terminal fragment of the VEEV capsid by its Sindbis virus-specific counterpart in the VEEV TC-83 genome does not affect virus replication in vitro but reduces cytopathogenicity and results in attenuation in vivo. These findings can be used in designing a new generation of live, attenuated, recombinant vaccines against the New World alphaviruses.

Quantitative Phosphoproteomics Identified a New Syk-Lyn-Axl Signalling Pathway Involved In Resistance to Nilotinib In Chronic Myeloid Leukemia Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3376-3376
Author(s):  
Romain Gioia ◽  
Cedric Leroy ◽  
Claire Drullion ◽  
Valérie Lagarde ◽  
Serge Roche ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Dependent Manner ◽  
Stable Isotope Labelling ◽  
Resistant Cells

Abstract Abstract 3376 Nilotinib has been developed to overcome resistance to imatinib, the first line treatment of chronic myeloid leukemia (CML). To anticipate resistance to nilotinib, we generate nilotinib resistant CML cell lines in vitro to characterize mechanisms and signaling pathways that may contribute to resistance. Among the different mechanisms of resistance identified, the overexpression of the Src-kinase Lyn was involved in resistance both in vitro, in a K562 cell line (K562-rn), and in vivo, in nilotinib-resistant CML patients. To characterize how Lyn mediates resistance, we performed a phosphoproteomic study using SILAC (Stable Isotope Labelling with Amino acid in Cell culture). Quantification and identification of phosphotyrosine proteins in the nilotinib resistant cells point out two tyrosine kinases, the spleen tyrosine kinase Syk and the UFO receptor Axl. The two tyrosine kinase Syk and Axl interact with Lyn as seen by coimmunopreciptation. Syk is phosphorylated on tyrosine 323 and 525/526 in Lyn dependent manner in nilotinib resistant cells. The inhibition of Syk tyrosine kinase by R406 or BAY31-6606 restores sensitivity to nilotinib in K562-rn cells. In parallel, the inhibition of Syk expression by ShRNA in K562-rn cells abolishes Lyn and Axl phosphorylation and then interaction between Lyn and Axl leading to a full restoration of nilotinib efficacy. In the opposite, the coexpression of Lyn and Syk in nilotinib sensitive K562 cells induced resistance to nilotinib whereas a Syk kinase dead mutant did not. These results highlight for the first time the critical role of Syk in resistance to tyrosine kinase inhibitors in CML disease emphasizing the therapeutic targeting of this tyrosine kinase. Moreover, Axl, which is already a target in solid tumor, will be also an interesting pathway to target in CML. Disclosures: No relevant conflicts of interest to declare.

STIM1 Deficiency Results In Impaired Platelet Procoagulant Activity and Protection From Arterial Thrombosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 485-485
Author(s):  
Firdos Ahmad ◽  
Lucia Stefanini ◽  
Timothy Daniel Ouellette ◽  
Teshell K Greene ◽  
Stefan Feske ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Critical Role ◽  
Phosphatidyl Serine ◽  
Flow Chamber ◽  
Procoagulant Activity ◽  
Static Conditions

Abstract Abstract 485 Platelet activation is a central event in thrombosis and hemostasis. We recently demonstrated that most aspects of platelet activation depend on synergistic signaling by two signaling modules: 1) Ca2+/CalDAG-GEFI/Rap1 and 2) PKC/P2Y12/Rap1. The intracellular Ca2+ concentration of platelets is regulated by Ca2+ release from the endoplasmic reticulum (ER) and store-operated calcium entry (SOCE) through the plasma membrane. Stromal interaction molecule 1 (STIM1) was recently identified as the ER Ca2+ sensor that couples Ca2+ store release to SOCE. In this study, we compared the activation response of platelets lacking STIM1−/− or CalDAG-GEFI−/−, both in vitro and in vivo. To specifically investigate Ca2+-dependent platelet activation, some of the experiments were performed in the presence of inhibitors to P2Y12. The murine Stim1 gene was deleted in the megakaryocyte/platelet lineage by breeding Stim flox/flox mice with PF4-Cre mice (STIM1fl/fl). STIM1fl/fl platelets showed markedly reduced SOCE in response to agonist stimulation. aIIbβ3 activation in STIM1fl/fl platelets was significantly reduced in the presence but not in the absence of the P2Y12 inhibitor, 2-MesAMP. In contrast, aIIbb3 activation was completely inhibited in 2-MesAMP-treated CalDAG-GEFI−/− platelets. Deficiency in STIM1, and to a lesser extent in CalDAG-GEFI, reduced phosphatidyl serine (PS) exposure in platelets stimulated under static conditions. PS exposure was completely abolished in both STIM1fl/fl and CalDAG-GEFI−/− platelets stimulated in the presence of 2-MesAMP. To test the ability of platelets to form thrombi under conditions of arterial shear stress, we performed flow chamber experiments with anticoagulated blood perfused over a collagen surface. Thrombus formation was abolished in CalDAG-GEFI−/− blood and WT blood treated with 2-MesAMP. In contrast, STIM1fl/fl platelets were indistinguishable from WT platelets in their ability to form thrombi. STIM1fl/fl platelets, however, were impaired in their ability to express PS when adhering to collagen under flow. Consistently, when subjected to a laser injury thrombosis model, STIM1fl/fl mice showed delayed and reduced fibrin generation, resulting in the formation of unstable thrombi. In conclusion, our studies indicate a critical role of STIM1 in SOCE and platelet procoagulant activity, but not in CalDAG-GEFI mediated activation of aIIbb3 integrin. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document