Cytoskeletal regulation of platelet formation: Coordination of F-actin and microtubules

Poulter, Natalie S.; Thomas, Steven G.

doi:10.1016/j.biocel.2015.07.008

Cited by 49 publications

(61 citation statements)

References 53 publications

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“…Platelet counts were always low in Patient 1, low (for example, 79 × 10 9 l −1 ) to normal in Patient 2, and normal in Patient 3 (Table 1). The microthrombocytes we observed in all three patients suggest that decreased ARPC1B in MKs affects the cytoskeletal dynamics of platelet formation4248 sufficiently to influence platelet size. The thrombocytopenia observed in Patient 1 indicates that total loss of ARPC1B leads to depression of platelet production and/or increased clearance.…”

Section: Resultsmentioning

confidence: 71%

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

et al. 2017

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Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two ARPC1 component isoforms, with ARPC1B prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in ARPC1B (p.Val91Trpfs*30). Platelet lysates reveal no ARPC1B protein and greatly reduced Arp2/3 complex. Missense ARPC1B mutations are identified in an unrelated patient with similar symptoms and ARPC1B deficiency. ARPC1B-deficient platelets are microthrombocytes similar to those seen in Wiskott–Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of ARPC1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased ARPC1A expression. Thus loss of ARPC1B produces a unique set of platelet abnormalities, and is associated with haematopoietic/immune symptoms affecting cell lineages where this isoform predominates. In agreement with recent experimental studies, our findings suggest that ARPC1 isoforms are not functionally interchangeable.

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Section: Resultsmentioning

confidence: 71%

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

et al. 2017

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“…Thrombopoietin (TPO) is the main humoral driver of megakaryopoiesis 5, 6. However, TPO does not regulate proplatelet formation,7 a process requiring complex remodelling of cytoskeletal elements, including actin and microtubules 8, 9…”

Section: Introductionmentioning

confidence: 99%

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

Kamal

Green

Hearn

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Intracellular calcium pathways regulate megakaryopoiesis but details are unclear.We examined effects of NMDAR‐mediated calcium influx on normal and leukemic cells in culture.NMDARs facilitated differentiation of normal but proliferation of leukemic megakaryocytes.NMDAR inhibitors induced differentiation of leukemic Meg‐01 cells. Background N‐methyl‐d‐aspartate receptors (NMDARs) contribute calcium influx in megakaryocytic cells but their roles remain unclear; both pro‐ and anti‐differentiating effects have been shown in different contexts.ObjectivesThe aim of this study was to clarify NMDAR contribution to megakaryocytic differentiation in both normal and leukemic cells.MethodsMeg‐01, Set‐2, and K‐562 leukemic cell lines were differentiated using phorbol‐12‐myristate‐13‐acetate (PMA, 10 nmol L−1) or valproic acid (VPA, 500 μmol L−1). Normal megakaryocytes were grown from mouse marrow‐derived hematopoietic progenitors (lineage‐negative and CD41a‐enriched) in the presence of thrombopoietin (30‐40 nmol L−1). Marrow explants were used to monitor proplatelet formation in the native bone marrow milieu. In all culture systems, NMDARs were inhibited using memantine and MK‐801 (100 μmol L−1); their effects compared against appropriate controls.ResultsThe most striking observation from our studies was that NMDAR antagonists markedly inhibited proplatelet formation in all primary cultures employed. Proplatelets were either absent (in the presence of memantine) or short, broad and intertwined (with MK‐801). Earlier steps of megakaryocytic differentiation (acquisition of CD41a and nuclear ploidy) were maintained, albeit reduced. In contrast, in leukemic Meg‐01 cells, NMDAR antagonists inhibited differentiation in the presence of PMA and VPA but induced differentiation when applied by themselves.Conclusions NMDAR‐mediated calcium influx is required for normal megakaryocytic differentiation, in particular proplatelet formation. However, in leukemic cells, the main NMDAR role is to inhibit differentiation, suggesting diversion of NMDAR activity to support leukemia growth. Further elucidation of the NMDAR and calcium pathways in megakaryocytic cells may suggest novel ways to modulate abnormal megakaryopoiesis.

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“…6 Cytoskeletal rearrangement is critical during megakaryocyte maturation, as evidenced by the fact that disruption of microtubules or F-actin dynamics results in profound defects in proplatelet formation. 7 Once released into the blood stream, platelets can circulate in a non-adhesive state for ~10 and 5 days in humans and mice, respectively, unless they are consumed by the hemostatic process. Platelet homeostasis, i.e.…”

Section: Introductionmentioning

confidence: 99%

Deletion of the Arp2/3 complex in megakaryocytes leads to microthrombocytopenia in mice

Paul¹,

Casari²,

Wu³

et al. 2017

Blood Advances

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Actin reorganization regulates key processes in platelet activation. Here we examined the role of the Arp2/3 complex, an essential component in actin filament branching, in platelet function. The Arpc2 gene, encoding the p34 subunit of the Arp2/3 complex, was deleted in the megakaryocyte lineage (Arpc2fl/flPF4-Cre). Deletion of the Arp2/3 complex resulted in marked microthrombocytopenia in mice, caused by premature platelet release into the bone marrow compartment and impaired platelet survival in circulation. Arpc2fl/flPF4-Cre platelets exhibited alterations in their actin cytoskeleton and their peripheral microtubule coil. Thrombocytopenia was alleviated following clodronate liposome-induced macrophage depletion in Arpc2fl/flPF4-Cre mice. Arpc2fl/flPF4-Cre platelets failed to spread and showed a mild defect in integrin activation and aggregation. However, no significant differences in hemostasis or thrombosis were observed between Arpc2fl/flPF4-Cre and control mice. Thus, Arp2/3 is critical for platelet homeostasis but plays only a minor role for vascular hemostasis.

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Cytoskeletal regulation of platelet formation: Coordination of F-actin and microtubules

Cited by 49 publications

References 53 publications

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

Deletion of the Arp2/3 complex in megakaryocytes leads to microthrombocytopenia in mice

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