Blood Adv. 2020 Jul 14;4(13):3011-3023. doi: 10.1182/bloodadvances.2020001758. | PubMed

Shauna L French¹, Kirill R Butov^2,3, Isabelle Allaeys⁴, Jorge Canas⁵, Golnaz Morad^6,7, Patricia Davenport⁵, Audrée Laroche⁴, Natalia M Trubina^2,3, Joseph E Italiano^1,6,8, Marsha A Moses^6,8, Martha Sola-Visner⁵, Eric Boilard⁴, Mikhail A Panteleev^2,3, Kellie R Machlus¹

1. Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA.
2. Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
3. Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia.
4. Département de Microbiologie et Immunologie, Faculté de Médecine de l'Université Laval, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.
5. Division of Newborn Medicine and.
6. Vascular Biology Program, Boston Children's Hospital, Boston, MA.
7. Graduate School of Arts and Sciences, Harvard University, Cambridge, MA; and.
8. Department of Surgery, Harvard Medical School, Boston, MA.

Abstract

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.

Presented By Kellie Machlus