title: Thrombopoietin/TGF-β1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis.
abstract: Extracellular matrix (ECM) components initiate crucial biochemical and biomechanical cues that are required for bone marrow homeostasis. In our research, we prove that a peri-cellular matrix composed primarily of type III and type IV collagens, and fibronectin surrounds human megakaryocytes in the bone marrow. The data we collected support the hypothesis that bone marrow megakaryocytes possess a complete mechanism to synthesize the ECM components, and that thrombopoietin is a pivotal regulator of this new function inducing transforming growth factor-β1 (TGF-β1) release and consequent activation of the downstream pathways, both in vitro and in vivo. This activation results in a dose dependent increase of ECM component synthesis by megakaryocytes, which is reverted upon incubation with JAK and TGF-β1 receptor specific inhibitors. These data are pivotal for understanding the central role of megakaryocytes in creating their own regulatory niche within the bone marrow environment.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Abbonante
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Di Buduo
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Gruppi
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malara
authors.affiliation: Hematopathology Service, Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Gianelli
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Celesti
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Anselmo
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.affiliation: Center for Tissue Engineering (CIT), INSTM UdR of Pavia, University of Pavia, Pavia, Italy.|Department of Occupational Medicine, Ergonomics and Disability, Salvatore Maugeri Foundation (FSM), Laboratory of Nanotechnology, Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vercellino
authors.affiliation: Center for Tissue Engineering (CIT), INSTM UdR of Pavia, University of Pavia, Pavia, Italy.|Department of Occupational Medicine, Ergonomics and Disability, Salvatore Maugeri Foundation (FSM), Laboratory of Nanotechnology, Pavia, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Visai
authors.affiliation: Oncohematology of the Elderly Unit, Oncohematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Iurlo
authors.affiliation: Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Remigio
authors.initials: R
authors.lastname: Moratti
authors.affiliation: Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy.|Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduini
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000254:growth & development / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D024061:Collagen Type III; D024141:Collagen Type IV; D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013926:Thrombopoietin; D053612:Janus Kinases
keywords: Bone marrow; Extracellular matrix; Megakaryocytes; Thrombopoietin; Transforming growth factor-β1