Platelet-derived microparticles enhance megakaryocyte differentiation and platelet generation via miR-1915-3p

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.

Horizontal MicroRNA Transfer by Platelets – Evidence and Implications

“…An important role for PMV-derived miRNAs in the regulation of thrombopoiesis during increased platelet consumption and replenishment was identified in a mouse model of carbon tetrachloride-induced liver injury. In this paper, injection of PMV, which were highly enriched in miR-1915-39, led to TPO-independent increase of megakaryocytes and platelets by suppressing a member of the Rho GTPase family in hematopoietic stem cells ( Qu et al, 2020 ).…”

Platelets in ITP: Victims in Charge of Their Own Fate?

“…Interestingly, however, accumulating literature suggests that PMPs also have immune-modulating functions and might be involved in the development of autoimmune mediated diseases such as SLE and RA [52,53]. Furthermore, PMPs were shown to infiltrate the bone marrow during inflammation and to alter megakaryopoiesis [54,55]. Given these findings, we hypothesize that PMPs play a role in the pathogenesis of ITP in two ways: (1) by stimulating immune cells such as B cells, T cells and monocytes in a pro-inflammatory manner and (2) by impairing the function of megakaryocytes in the bone marrow which causes defects in the platelet production (see Figures 1 and 2).…”

“…Hence, it is plausible that platelets in ITP have aberrant intra-and extracellular compounds that they can transfer to their PMPs. Furthermore, PMPs have been reported to enhance megakaryopoiesis in thrombocytopenic mice with acute liver injury [55]. Despite the increased number of PMPs in ITP, megakaryopoiesis appears to be impaired, implying that the PMP cargo could be altered in ITP.…”

“…PMPs can infiltrate the bone marrow during inflammatory conditions and interact with and reprogram megakaryocytes [54,55,98]. In mice with acute liver injury-induced thrombocytopenia, PMPs have been demonstrated to promote megakaryopoiesis leading to elevated platelet production [55].…”

“…PMPs can infiltrate the bone marrow during inflammatory conditions and interact with and reprogram megakaryocytes [54,55,98]. In mice with acute liver injury-induced thrombocytopenia, PMPs have been demonstrated to promote megakaryopoiesis leading to elevated platelet production [55]. In addition, it was shown that PMPs transfer specific miRNAs (e.g., miRNA-1915-3p) to MKs leading to MK proliferation, differentiation and platelet production [11,55].…”