Platelet-derived extracellular vesicles infiltrate and modify the bone marrow during inflammation

Abstract

<jats:title>Abstract</jats:title> <jats:p>During inflammation, steady-state hematopoiesis switches to emergency hematopoiesis to repopulate myeloid cells, with a bias toward the megakaryocytic lineage. Soluble inflammatory cues are thought to be largely responsible for these alterations. However, how these plasma factors rapidly alter the bone marrow (BM) is not understood. Inflammation also drives platelet activation, causing the release of platelet-derived extracellular vesicles (PEVs), which package diverse cargo and reprogram target cells. We hypothesized that PEVs infiltrate the BM, providing a direct mode of communication between the plasma and BM environments. We transfused fluorescent, wild-type (MPL+) platelets into recipient cMpl−/−mice before triggering systemic inflammation. Twenty hours postinfusion, we observed significant infiltration of donor platelet-derived particles in the BM, which we tracked immunophenotypically (MPL+ immunohistochemistry staining) and quantified by flow cytometry. To determine if this phenomenon relates to humans, we extensively characterized both megakaryocyte-derived and PEVs generated in vitro and in vivo, and found enrichment of extracellular vesicles in bone marrow compared with autologous peripheral blood. Last, BM from cMpl−/− mice was cultured in the presence or absence of wild-type (MPL+) PEVs. After 72 hours, flow cytometry revealed increased megakaryocytes only in cultures with added PEVs. The majority of CD41+ cells were bound to PEVs, suggesting a PEV-mediated rescue of megakaryopoiesis. In conclusion, we report for the first time that plasma-residing PEVs infiltrate the BM. Further, PEVs interact with BM cells in vivo and in vitro, causing functional reprogramming that may represent a novel model of inflammation-induced hematopoiesis.</jats:p>

Is there a role for the ACE2 receptor in SARS‐CoV‐2 interactions with platelets?

“…In addition to direct virus interaction with megakaryocytes and platelets, it is possible SARS-CoV-2 virus released into extracellular vesicles from infected white blood cells or endothelial cells can be internalized by platelets, resulting in SARS-CoV-2 virus positive platelets through indirect uptake of viral particles contained inside extracellular vesicles. [45][46][47][48]…”

The multifaceted contribution of platelets in the emergence and aftermath of acute cardiovascular events

“…These EVs have the potential to modulate biologic processes distal from the site of platelet activation [47,48]. So far, platelet-derived EVs have been demonstrated to enhance the recruitment of monocytes and neutrophils to the vessel wall during inflammation [49,50]; deposit chemokines that trigger the recruitment of monocytes [51]; directly promote monocyte differentiation into macrophages [52]; alter macrophage genotype and function [53,54]; induce proliferation and transformation of smooth muscle cells to a pro-inflammatory phenotype [55]; upon infiltrating the bone marrow, modulate the behavior of megakaryocytes to alter thrombopoiesis during inflammation [56]. Although these observations might be explained by the action of proteins and lipids carried by EVs, a number of interesting studies have also pointed towards nucleic acids, notably microRNAs (miR), as molecular effectors.…”

Extracellular tyrosyl‐tRNA synthetase cleaved by plasma proteinases and stored in platelet α‐granules: Potential role in monocyte activation

“…Alternatively, recent studies have shown that aaRSs can be secreted via exosomes, and therefore we cannot exclude the possibility that YRS is present in such vesicles in plasma 27 . Interestingly, it has recently been reported that platelet‐derived extracellular vesicles (PEVs) infiltrate the bone marrow during inflammation and provide direct communication of plasma components with bone marrow cells 28 . It is possible that PEVs contain active form of endogenous YRS protein (eg, YRS Mini+ ) and infiltrate the bone marrow, where it stimulates megakaryopoiesis under inflammatory stress conditions.…”