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.
Highlights
Thrombosis leads to platelet activation and subsequent degradation; replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to maintain the physiological level of circulating platelets
It has been reported that MPs from macrophages induced macrophage differentiation from naïve monocytes[2] and MPs from megakaryocytes (MKMPs)[3] promoted HSPC differentiation to mature megakaryocytes (MKs)
Thereafter, we investigated whether the percentage of activated platelets and the number of MPs in the peripheral blood (PB) of acute liver injury (ALI) mice increased before the increase in megakaryocytic cell proportion in the bone marrow (BM) and the enhancement of platelet count in the PB
Summary
Thrombosis leads to platelet activation and subsequent degradation; replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to maintain the physiological level of circulating platelets. Our data reveal that PMPs have a role in promoting megakaryocytic differentiation and platelet production. The activated platelets release MPs, some of which can be internalized by HSPCs and drive the cells toward a megakaryocytic fate. We demonstrate that PMPs can promote MK differentiation and platelet production and reveal the underlying mechanism. MiRNA is one of the abundant contents of PMPs. Elaborated miRNA analysis revealed that, a miRNA highly enriched in PMPs, miR-1915-3p, can be transported to target cells and suppress RHOB expression, thereby induces megakaryocytic differentiation. In vivo and in vitro studies of PMPs suggest that a potential feedback loop is involved in the regulation of platelet numbers, complementary to the typical platelet regulation theory in which physiological and pathological platelet generation is regulated by TPO. The important role of PMPs in MK feedback regulation might expand our knowledge of lineage homeostasis
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