期刊
JOURNAL OF CONTROLLED RELEASE
卷 247, 期 -, 页码 1-18出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2016.12.021
关键词
Microparticle; Extracellular vesicle; Stem cell; Megakaryocytic
资金
- National Institutes of Health grant [R21HL106397]
- State of Delaware CAT grant [15A01570]
- National Institute of GeneralMedical Sciences-NIGMS from the National Institutes of Health [5 P30 GM110758-02]
- National Institutes of Health
Megakaryocytic microparticles (MkMPs), the most abundant MPs in circulation, can induce the differentiation of hematopoietic stem and progenitor cells (HSPCs) into functional megakaryocytes. This MkMP capability could be explored for applications in transfusion medicine but also for delivery of nucleic acids and other molecules to HSPCs for targeted molecular therapy. Understanding how MkMPs target, deliver cargo and alter the fate of HSPCs is important for exploring such applications. We show that MkMPs, which are distinct from Mk exosomes (MkExos), target HSPCs with high specificity since they have no effect on other ontologically or physiologically related cells, namely mesenchymal stem cells, endothelial cells or granulocytes. The outcome is also specific: only cells of the megakaryocytic lineage are generated. Observation of intact fluorescently-tagged MkMPs inside HSPCs demonstrates endocytosis as one mechanismof cargo delivery. Fluorescent labeling and scanning electron microscopy (SEM) imaging show that direct fusion of MkMPs into HSPCs is also engaged in cargo delivery. SEM imaging detailed the membrane-fusion process in four stages leading to full adsorption of MkMPs into HSPCs. Furthermore, macropinocytosis and lipid raft-mediated were shown here as mechanisms of MkMP uptake by HSPC. In contrast, the ontologically related platelet-derived MPs (PMPs) cannot be taken up by HSPCs although they bind to and induce HSPC aggregation. We show that platelet-like thrombin activation is apparently responsible for the different biological effects of MkMPs versus PMPs on HSPCs. We show that HSPC uropods are the preferential site for MkMP binding, and that CD54 (ICAM-1), CD11b, CD18 and CD43, localized on HSPC uropods, are involved in MkMP binding to HSPCs. Finally, we show that MkMP RNA is largely responsible for HSPC programming into Mk differentiation. (C) 2016 Elsevier B.V. All rights reserved.
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