In vivo inhibition of megakaryocyte and platelet production by platelet factor 4 in mice.
9
Citation
0
Reference
10
Related Paper
Abstract:
The in vivo effect of human platelet factor 4 (PF4) on murine megakaryocytopoiesis and thrombopoiesis was studied. Administration of PF4 induced a dose-dependent decrease in the numbers of megakaryocytes and their progenitor cells (CFU-MK), continuing for 1 week after the injection. However, the size of megakaryocytes and their colonies was not changed following PF4 injection. Platelet levels were significantly decreased at days 3-4. The number of CFU-GM was decreased at days 1-2. White blood cells and hemoglobin were unaffected by PF4. These data indicate that PF4 inhibits megakaryocyte and platelet production in vivo by acting on the early stage of megakaryocyte development.Keywords:
Thrombopoiesis
Megakaryocytopoiesis
Ex vivo
Cite
Thrombopoiesis
Ex vivo
Megakaryocytopoiesis
Platelet disorder
Cite
Citations (0)
Thrombopoiesis
Megakaryocytopoiesis
Blood cell
Cite
Citations (2)
The in vivo effect of human platelet factor 4 (PF4) on murine megakaryocytopoiesis and thrombopoiesis was studied. Administration of PF4 induced a dose-dependent decrease in the numbers of megakaryocytes and their progenitor cells (CFU-MK), continuing for 1 week after the injection. However, the size of megakaryocytes and their colonies was not changed following PF4 injection. Platelet levels were significantly decreased at days 3-4. The number of CFU-GM was decreased at days 1-2. White blood cells and hemoglobin were unaffected by PF4. These data indicate that PF4 inhibits megakaryocyte and platelet production in vivo by acting on the early stage of megakaryocyte development.
Thrombopoiesis
Megakaryocytopoiesis
Ex vivo
Cite
Citations (9)
Abstract Thrombosis leads to platelet activation and subsequent degradation; therefore, replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to maintain the physiological level of circulating platelets. Platelet-derived microparticles (PMPs) are protein- and RNA-containing vesicles released from activated platelets. We hypothesized that factors carried by PMPs might influence the production of platelets from HSPCs, in a positive feedback fashion. Here we show that, during mouse acute liver injury, the density of megakaryocyte in the bone marrow increases following an increase in circulating PMPs, but without thrombopoietin (TPO) upregulation. In vitro, PMPs are internalized by HSPCs and drive them toward a megakaryocytic fate. Mechanistically, miR-1915-3p, a miRNA highly enriched in PMPs, is transported to target cells and suppresses the expression levels of Rho GTPase family member B, thereby inducing megakaryopoiesis. In addition, direct injection of PMPs into irradiated mice increases the number of megakaryocytes and platelets without affecting TPO levels. In conclusion, our data reveal that PMPs have a role in promoting megakaryocytic differentiation and platelet production.
Thrombopoiesis
Megakaryocytopoiesis
Cite
Citations (68)
Megakaryocytopoiesis
Thrombopoiesis
Progenitor
Cite
Citations (172)
To evaluate whether the continuous treatment of two cytokine combinations is effective in megakaryocytopoiesis and thrombopoiesis in hematopoietic stem/progenitor cells exposed to heavy ion beams, the effects of a 2-step culture by a combination of recombinant human interleukin-3 (IL-3) + stem cell factor (SCF) + thrombopoietin (TPO), which just slightly protected against carbon-ion beam-induced damages, and a combination of IL-3 + TPO, which selectively stimulated the differentiation of the hematopoietic stem/progenitor cells to megakaryocytes and platelets, were examined. CD34+-hematopoietic stem/progenitor cells isolated from the human placental and umbilical cord blood were exposed to carbon-ion beams (LET = 50 keV/μm) at 2 Gy. These cells were cultured under three cytokine conditions. The number of megakaryocytes, platelets and hematopoietic progenitors were assessed using a flow cytometer and a clonogenic assay at 14 and 21 days after irradiation, respectively. However, the efficacy of each 2-step culture was equal or lower than that of using the IL-3 + SCF + TPO combination alone and the 2-step culture could not induce megakaryocytes and platelets from hematopoietic stem/progenitor cells exposed to high LET-radiation such as carbon-ion beams. Therefore, additional cytokines and/or hematopoietic promoting compounds might be required to overcome damage to hematopoietic cells by high LET radiation.
Megakaryocytopoiesis
Thrombopoiesis
Cite
Citations (6)
Megakaryocytopoiesis
Thrombopoiesis
Granulopoiesis
Thrombocytosis
Cite
Citations (16)
Platelet transfusions are used to treat idiopathic or drug-induced thrombocytopenia. Platelets are an expensive product in limited supply, with limited storage and distribution capabilities because they cannot be frozen. We have demonstrated that, in vitro, human megakaryocytic microparticles (huMkMPs) target human CD34+ hematopoietic stem and progenitor cells (huHSPCs) and induce their Mk differentiation and platelet biogenesis in the absence of thrombopoietin. In this study, we showed that, in vitro, huMkMPs can also target murine HSPCs (muHSPCs) to induce them to differentiate into megakaryocytes in the absence of thrombopoietin. Based on that, using wild-type BALB/c mice, we demonstrated that intravenously administering 2 × 106 huMkMPs triggered de novo murine platelet biogenesis to increase platelet levels up to 49% 16 hours after administration. huMkMPs also largely rescued low platelet levels in mice with induced thrombocytopenia 16 hours after administration by increasing platelet counts by 51%, compared with platelet counts in thrombocytopenic mice. Normalized on a tissue-mass basis, biodistribution experiments show that MkMPs localized largely to the bone marrow, lungs, and liver 24 hours after huMkMP administration. Beyond the bone marrow, CD41+ (megakaryocytes and Mk-progenitor) cells were frequent in lungs, spleen, and especially, liver. In the liver, infused huMKMPs colocalized with Mk progenitors and muHSPCs, thus suggesting that huMkMPs interact with muHSPCs in vivo to induce platelet biogenesis. Our data demonstrate the potential of huMkMPs, which can be stored frozen, to treat thrombocytopenias and serve as effective carriers for in vivo, target-specific cargo delivery to HSPCs.
Cite
Citations (24)
Blood agencies worldwide face the same recurring problem of enrolling healthy donors to produce platelet concentrates ( PC ) to meet the fluctuating demand. Research in stem cell biology has now made possible the production of culture‐derived platelets ( CDP ) raising the possibility of producing donor‐independent platelets. The aim of this paper was to first review known key concepts about megakaryopoiesis and second to describe efforts done in our laboratory and that of others for the establishment of culture processes for the production of megakaryocytes and platelets from cord blood haematopoietic stem and progenitor cells ( HSPC ). Recent progresses made with induced pluripotent stem cells ( iPSC s) are also presented. Expansion of HSPC s and megakaryocytes can be accomplished by combining thrombopoietin ( TPO ) and a wide array of other cytokines. However, expansion of HSPC s ex vivo is associated with a rapid loss of megakaryocyte differentiation potential. Optimization of cytokine combinations and concentrations can improve yields and reduce consumption of growth factors. Moreover, the development of inducible megakaryocytic cell lines that can be triggered to undergo terminal megakaryocytic differentiation offers an independent solution to some of the problems associated with megakaryocyte production ex vivo . Functional characterization of platelets produced ex vivo has so far revealed that they form a heterogeneous population with some culture‐derived platelets (CDP) showing normal platelet properties and functions. In summary, functional CDP s can be produced in HSPC ‐ and iPSC ‐based cultures. Remaining challenges that need to be addressed before culture‐derived PC s can be used to complement blood‐derived PC s are also discussed.
Thrombopoiesis
Ex vivo
Cord blood
Megakaryocytopoiesis
Cite
Citations (10)
Megakaryocytopoiesis
Progenitor
Thrombopoiesis
Cite
Citations (5)