title: Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation.
abstract: Liver regeneration is stimulated by blood platelets, but the molecular mechanisms involved are largely unexplored. Although platelets are anucleate, they do contain coding or regulatory RNAs that can be functional within the platelet or, after transfer, in other cell types. Here, we show that platelets and platelet-like particles (PLPs) derived from the megakaryoblastic cell line MEG-01 stimulate proliferation of HepG2 cells. Platelets or PLPs were internalized within 1 hour by HepG2 cells and accumulated in the perinuclear region of the hepatocyte. Platelet internalization also occurred following a partial hepatectomy in mice. Annexin A5 blocked platelet internalization and HepG2 proliferation. We labeled total RNA of MEG-01 cells by incorporation of 5-ethynyluridine (EU) and added EU-labeled PLPs to HepG2 cells. PLP-derived RNA was detected in the cytoplasm of the HepG2 cell. We next generated PLPs containing green fluorescent protein (GFP)-tagged actin messenger RNA. PLPs did not synthesize GFP, but in coculture with HepG2 cells, significant GFP protein synthesis was demonstrated. RNA-degrading enzymes partly blocked the stimulating effect of platelets on hepatocyte proliferation. Thus, platelets stimulate hepatocyte proliferation via a mechanism that is dependent on platelet internalization by hepatocytes followed by functional transfer of RNA stored in the anucleate platelet. This mechanism may contribute to platelet-mediated liver regeneration.
authors.affiliation: Surgical Research Laboratory.
authors.forename: Marc
authors.initials: M
authors.lastname: Kirschbaum
authors.affiliation: Surgical Research Laboratory.
authors.forename: Golnar
authors.initials: G
authors.lastname: Karimian
authors.affiliation: Surgical Research Laboratory.
authors.forename: Jelle
authors.initials: J
authors.lastname: Adelmeijer
authors.affiliation: Department of Cell Biology, and.
authors.forename: Ben N G
authors.initials: BN
authors.lastname: Giepmans
authors.affiliation: Section of Hepatobiliairy Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Porte
authors.affiliation: Surgical Research Laboratory, Section of Hepatobiliairy Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ton
authors.initials: T
authors.lastname: Lisman
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D015870:Gene Expression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D034443:RNA Transport / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D014498:Uracil / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000199:Actins; D017304:Annexin A5; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; C073482:eniluracil; D014498:Uracil