megakaryocyte development and platelet production

Milestones in understanding platelet production: a historical overview. Platelet procoagulant activity and microvesicle formation. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C.

Cytoskeletal mechanics of proplatelet maturation and platelet release.  | 

Additionally, peripheral platelets expand correspondingly and exhibit normal function and viability during the ensuing 10 days. The life span of autologous 111In-labeled platelets increased from 205 ± 18 hours (baseline) to 226 ± 22 hours (P < .01) on day 8. A sixfold increase in the number of megakaryocytes was determined visually in bone marrow samples and ploidy was skewed to 32N. Each subject had 2 bone marrow studies, ie, either baseline and at day 12, or day 8 and day 18. Whether prosurvival and proapoptotic proteins have any role in determining surface sialic acid content is unknown. Mean TPO receptor numbers per platelet were estimated from platelet-binding isotherms of 125I-labeled recombinant human (rHu) TPO according to Scatchard analysis.18,19 In brief, TPO receptors on platelets were determined using purified rHu-TPO radiolabeled by Iodo-beads iodination reagent (Pierce, Rockford, IL), and incubating rHu-TPO with 50 mmol/L sodium phosphate buffer, pH 7.2, and 125I with Iodo-beads for 15 minutes. Megakaryopoiesis is the process by which a hematopoietic progenitor cell (HPC) differentiates into a large polyploid megakaryocyte, whereas thrombopoiesis is the process by which platelets are released from megakaryocytes.4  As megakaryocytes mature in the bone marrow, the nucleus becomes multilobed by endomitosis and the cytoplasm undergoes an increase in volume. Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. Please enable it to take advantage of the complete set of features! Megakaryocyte yield can be increased by the development of a self-replicating megakaryocyte progenitor system. Finally, we consider how insights gained from knockout (KO) animal models and human diseases have increased our understanding of megakaryocyte development and platelet formation.
provided expertise in the field as well as scientific direction and revised drafts; P.G. Evidence of both impaired platelet production and increased platelet clearance. Platelet populations enriched with newly formed platelets on day 8 demonstrate upward bowing of the disappearance curve with a computed life span of 226 ± 22 hours.

This study demonstrates that administering single bolus subcutaneous PEG-rHuMGDF (3 μg/kg) to healthy human volunteers doubles the peripheral platelet concentration by stimulating megakaryocyte proliferation and endoreduplication, thereby doubling the mass of megakaryocyte cytoplasm destined for release as circulating platelets, without modifying platelet viability, platelet responsiveness to physiologic agonists, or platelet expression of activation epitopes. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. Sphingosine kinase 2 (Sphk2) regulates platelet biogenesis by providing intracellular sphingosine 1-phosphate (S1P).

The initial condition for the ithmegakaryocyte compartment, Mi(0), was calculated as: where C0 is the serum concentration of Mpl ligand at baseline. One pool, comparable in size, yield, half-life, and function to donor-derived platelets, was generated from the infused megakaryocytes after a few hours delay. Platelet factors predisposing to arterial thrombosis. Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation. A major stumbling block in this process is maintaining megakaryocyte viability during endomitosis and cytoplasmic maturation. GATA1-null mouse ESCs were differentiated to bipotential megakaryocyte erythroid progenitors (MEPs) that proliferated for several months without differentiating. 2013;8(3):e58123. This is suggested by an interesting study of a family with mild autosomal-dominant thrombocytopenia.45  The defect was identified as a cytochrome c variant that displayed normal redox potential, but enhanced proapoptotic activity. Challenges and promises for the development of donor-independent platelet transfusions. In vitro megakaryocyte production and platelet biogenesis: state of the art. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Laurence A. Harker, Lorin K. Roskos, Ulla M. Marzec, Richard A. Carter, Judith K. Cherry, Birgitta Sundell, Ellen N. Cheung, Dixon Terry, William Sheridan; Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers. Platelet kinetics in patients with bone marrow hypoplasia: evidence for a fixed platelet requirement. At higher Mpl ligand concentrations, the relationship between platelet production rate and serum Mpl ligand may be appropriately described by a sigmoidal concentration-response relationship, such as a logistic function that could describe full receptor occupancy.  |  Manipulation of the apoptotic pathway in PSCs may overcome some of these viability issues and improve megakaryocyte yield. Phospho-inositide-dependent kinase 1 regulates signal dependent translation in megakaryocytes and platelets. Each megakaryocyte produces a total of 1000 to 3000 platelets. Premature platelet shedding was observed in a patient’s bone marrow with the detection of intramedullary megakaryocyte nuclei and platelets. Destruction of peripheral platelets was modeled by random and senescent processes. c-Mpl ligand is a humoral regulator of megakaryocytopoiesis. Dose-response effects of pegylated human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and function in nonhuman primates. Biologic parameters such as the rate of megakaryocytopoiesis, differential release rates of platelets from megakaryocytes of different ploidy, and megakaryocyte death rate, are not directly identifiable from observations of platelet kinetics in blood, per se. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte. The GPIbα (CD42b) subunit of the von Willebrand factor GPIb-V-IX receptor complex functions in cellular adhesion46,47  and GPVI is one of the collagen receptors involved in signaling.48  The cleavage of the N-terminal domain of GPIbα (termed glycocalicin49 ), which occurs during platelet storage, was identified on mouse platelets that were induced to undergo mitochondrial damage.50  This study showed that GPIbα cleavage could be inhibited by the broad-spectrum metalloproteinase (MMP) inhibitor GM6001, improving platelet clearance and function.

In each sample, 2000 to 3000 megakaryocytes were analyzed. In healthy human volunteers, minimal reduction in MPV develops as the peripheral platelet counts are elevated (Table 1), consistent with previous reports in nonhuman primates regarding the reciprocal relationship between MPV and the peripheral concentration of platelets.48 Presumably, the blunted decrease in MPV observed in normal subjects (Table 1), compared with the greater reduction in nonhuman primates, is due to the striking difference in the relative total dose and duration of PEG-rHuMGDF administration. Supported in part by Amgen Inc, and in part by PHS Grant MO1-RR00039 from the General Clinical Research Centers Program, National Institutes of Health, National Center for Research Resources. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Megakaryocyte Development and Platelet Formation. Expression of the platelet sialidase Neu1 has been identified on the platelet surface following refrigeration, suggesting that treatment with sialidase inhibitors may improve survival of transfused platelets. In addition, we review the proplatelet theory of platelet biogenesis and discuss the cytoskeletal mechanics of platelet formation. By using this approach in mice26  and comparing the yield and half-life of platelets released from megakaryocytes generated from adult, fetal liver, and PSC-derived progenitors to donor-derived platelets, 2 pools of human platelets were detected. One study showed that the overexpression of Bcl-xL in human megakaryocytes increased proliferative capacity and survival.41  We have demonstrated that amplification of Bcl-xL increased the number of human megakaryocytes generated in vitro.42  Culturing Bak−/− murine fetal liver progenitors to megakaryocytes showed that in addition to 40% to 60% increased numbers of PPF megakaryocytes, these cells continued to be present in the culture over a 10-day period instead of following the normal pattern of disappearance after 5 days.37  A common pharmacologic inhibitor of the intrinsic apoptotic pathway is cyclosporine that prevents mitochondrial membrane permeabilization and apoptosis in a variety of cell types. Appearance of a megakaryocyte growth-promoting activity, megapoietin, during acute thrombocytopenia in the rabbit. Historical review: megakaryopoiesis and thrombopoiesis. The disappearance pattern of day 12 platelets resembles the baseline pattern. Immune Thrombocytopenia: Where Are We Now? Two major strategies exist in the literature for obtaining platelets from in vitro–derived megakaryocytes. Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional. The peripheral platelet concentration at time t was calculated as the sum of the platelet numbers within na age compartments divided by the peripheral platelet dilution volume, Vp. (A) Model prediction (solid line) of platelet response to PEG-rHuMGDF is overlaid on observed platelet counts (closed circles). Flow cytometric detection. NIH Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages. Vainchenker W, Debili N, Norol F, Wendling F. Schweiz Med Wochenschr. Conflict-of-interest disclosure: The authors declare no competing financial interests.
The role of apoptosis in megakaryocytes and platelets. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Megakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors.

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood 2004; 103:1364.

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