Regulation of platelet lifespan in the presence and absence of thrombopoietin signaling

Lebois, Marion; Dowling, Mark R.; Gangatirkar, Pradnya; Hodgkin, Philip D.; Kile, Benjamin T.; Alexander, Warren S.; Josefsson, Emma C.

doi:10.1111/jth.13397

Cited by 23 publications

(11 citation statements)

References 25 publications

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“…While no megakaryocyte-associated fibrosis 29 , 30 was observed in 4–5 week old Tpo Tg mice (data not shown), our data cannot exclude an effect on B-lymphopoiesis from altered environmental niches or competition for space arising from abnormal megakaryocyte number in the bone marrow and spleen as Mpl −/− mice have 10% of normal megakaryocyte and platelet numbers, while Tpo Tg mice have ~3.5-fold increased platelet counts with 3-fold elevated bone marrow and spleen megakaryocytes 7 , 15 , 31 (Supplementary Fig. S5b ).…”

Section: Discussionmentioning

confidence: 68%

Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling

Lebois

Sim

et al. 2017

Sci Rep

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Thrombopoietin (TPO) is the master cytokine regulator of megakaryopoiesis. In addition to regulation of megakaryocyte and platelet number, TPO is important for maintaining proper hematopoietic stem cell (HSC) function. It was previously shown that a number of lymphoid genes were upregulated in HSCs from Tpo −/− mice. We investigated if absent or enhanced TPO signaling would influence normal B-lymphopoiesis. Absent TPO signaling in Mpl −/− mice led to enrichment of a common lymphoid progenitor (CLP) signature in multipotential lineage-negative Sca-1+c-Kit+ (LSK) cells and an increase in CLP formation. Moreover, Mpl −/− mice exhibited increased numbers of PreB2 and immature B-cells in bone marrow and spleen, with an increased proportion of B-lymphoid cells in the G1 phase of the cell cycle. Conversely, elevated TPO signaling in Tpo Tg mice was associated with reduced B-lymphopoiesis. Although at steady state, peripheral blood lymphocyte counts were normal in both models, Mpl −/− Eµ-myc mice showed an enhanced preneoplastic phase with increased numbers of splenic PreB2 and immature B-cells, a reduced quiescent fraction, and augmented blood lymphocyte counts. Thus, although Mpl is not expressed on lymphoid cells, TPO signaling may indirectly influence B-lymphopoiesis and the preneoplastic state in Myc-driven B-cell lymphomagenesis by lineage priming in multipotential progenitor cells.

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Section: Discussionmentioning

confidence: 68%

Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling

Lebois

Sim

et al. 2017

Sci Rep

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“…Importantly, c-MPL -/mice can present two distinct phenotypes: one with extremely low platelet counts, approaching 3% of normal, and another with platelet counts approximately 14% of normal. 33,34 Our study only included c-MPL -/mice in the latter category. The mild reduction in the platelet half-life of our adult animals was consistent with two prior studies, but was quite different from the more severe reduction observed in newborn pups.…”

Section: Discussionmentioning

confidence: 99%

Developmental Stage–Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice

et al. 2017

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Congenital amegakaryocytic thrombocytopenia (CAMT) is a disorder caused by c-MPL mutations that impair thrombopoietin (TPO) signalling, resulting in a near-absence of megakaryocytes (MKs). While this phenotype is consistent in adults, neonates with CAMT can present with severe thrombocytopenia despite normal MK numbers. To investigate this, we characterized MKs and platelets in newborn c-MPL−/− mice. Liver MKs in c-MPL−/− neonates were reduced in number and size compared to WT age-matched MKs, and exhibited ultrastructural abnormalities not found in adult c-MPL−/− MKs. Platelet counts were lower in c-MPL−/− compared to WT mice at birth and did not increase over the first two weeks of life. In vivo biotinylation revealed a significant reduction in the platelet half-life of c-MPL−/− newborn mice (P2) compared to age-matched WT pups, which was not associated with ultrastructural abnormalities. Genetic deletion of the pro-apoptotic Bak did not rescue the severely reduced platelet half-life of c-MPL−/− newborn mice, suggesting that it was due to factors other than platelets entering apoptosis early. Indeed, adult GFP+ platelets transfused into thrombocytopenic c-MPL−/− P2 pups also had a shortened lifespan, indicating the importance of cell-extrinsic factors. In addition, neonatal platelets from WT and c-MPL−/− mice exhibited reduced P-selectin surface expression following stimulation compared to adult platelets of either genotype, and platelets from c-MPL−/− neonates exhibited reduced GPIIb/IIIa activation in response to thrombin compared to age-matched WT platelets. Taken together, our findings indicate that c-MPL deficiency is associated with abnormal maturation of neonatal MKs and developmental stage-specific defects in platelet function.

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“…Platelet pellets were prepared as previously described with minor modifications ( Lebois et al, 2016 ). Platelet-rich plasma was obtained by centrifugation at 125 × g for 8 min, followed by centrifugation of the supernatant buffy coat at 125 × g for 8 min.…”

Section: Methodsmentioning

confidence: 99%

D-dencichine Regulates Thrombopoiesis by Promoting Megakaryocyte Adhesion, Migration and Proplatelet Formation

Ding¹,

Wang

Fang³

et al. 2018

Front. Pharmacol.

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Life-threatening chemotherapy-induced thrombocytopenia can increase the risk of bleeding due to a dramatic low platelet count, which may limit or delay treatment schedules in cancer patients. The pressing need for the rapid alleviation of the symptoms of thrombocytopenia has prompted us to search for novel highly effective and safe thrombopoietic agents. Pharmacological investigations have indicated that dencichine can prevent and treat blood loss and increase the number of platelets. On the basis of the neurotoxicity of dencichine, D-dencichine is artificially synthesized in the laboratory. Our initial results showed that D-dencichine had potential to elevate peripheral platelet levels in mice with carboplatin-induced thrombocytopenia. However, the mechanisms of D-dencichine on thrombopoiesis have been poorly understood. In this study, we found that sequential administration of D-dencichine had a distinct ability to elevate numbers of reticulated platelets, and did not alter their clearance. Moreover, we demonstrated that D-dencichine was able to modulate the return of hematopoietic factors to normal levels, including thrombopoietin and IL-6. However, subsequent analysis revealed that D-dencichine treatment had no direct effects on megakaryocytes proliferation, differentiation, and polyploidization. Further in vitro studies, we demonstrated for the first time that D-dencichine significantly stimulated megakaryocyte adhesion, migration, and proplatelet formation in a dose-dependent manner through extracellular regulated protein kinases1/2 (ERK1/2) and v-akt murine thymoma viral oncogene homolog (AKT) signaling pathways. This study sufficiently characterized the role of the effects of D-dencichine treatment on the regulation of thrombopoiesis and provided a promising avenue for CIT treating.

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Regulation of platelet lifespan in the presence and absence of thrombopoietin signaling

Cited by 23 publications

References 25 publications

Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling

Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling

Developmental Stage–Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice

D-dencichine Regulates Thrombopoiesis by Promoting Megakaryocyte Adhesion, Migration and Proplatelet Formation

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