title: Angptl4 is upregulated under inflammatory conditions in the bone marrow of mice, expands myeloid progenitors, and accelerates reconstitution of platelets after myelosuppressive therapy.
abstract: BACKGROUND
  Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body.
  
  
  METHODS
  Using microarray studies, we found that Angptl4 is upregulated in the BM during systemic inflammation.
  
  
  RESULTS
  Recombinant murine Angptl4 (rmAngptl4) stimulated the proliferation of myeloid colony-forming units (CFUs) in vitro. Upon repeated in vivo injections, rmAngptl4 increased BM progenitor cell frequency and this was paralleled by a relative increase in phenotypically defined granulocyte-macrophage progenitors (GMPs). Furthermore, in vivo treatment with rmAngptl4 resulted in elevated platelet counts in steady-state mice while allowing a significant acceleration of reconstitution of platelets after myelosuppressive therapy. The administration of rmAngptl4 increased the number of CD61(+)CD41(low)-expressing megakaryocytes (MK) in the BM of steady-state and in the spleen of transplanted mice. Furthermore, rmAngptl4 improved the in vitro differentiation of immature MKs from hematopoietic stem and progenitor cells. Mechanistically, using a signal transducer and activator of transcription 3 (STAT3) reporter knockin model, we show that rmAngptl4 induces de novo STAT3 expression in immature MK which could be important for the effective expansion of MKs after myelosuppressive therapy.
  
  
  CONCLUSIONS
  Whereas the definitive role of Angptl4 in mediating the effects of lipopolysaccharide (LPS) on the BM has to be demonstrated by further studies involving multiple cytokine knockouts, our data suggest that Angptl4 plays a critical role during hematopoietic, especially megakaryopoietic, reconstitution following stem cell transplantation.
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. anne-2704@web.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Schumacher
authors.affiliation: Interdisciplinary Center for Clinical Research IZKF Aachen, RWTH Aachen University Hospital, Aachen, Germany. bdenecke@ukaachen.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Denecke
authors.affiliation: Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. tbraunschweig@ukaachen.de.
authors.forename: Till
authors.initials: T
authors.lastname: Braunschweig
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. jstahlschmid@ukaachen.de.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Stahlschmidt
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. sziegler@ukaachen.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany. lbrandenburg@ukaachen.de.
authors.forename: Lars-Ove
authors.initials: LO
authors.lastname: Brandenburg
authors.affiliation: Department of Urology, University Medicine Greifswald, Greifswald, Germany. stopem@uni-greifswald.de.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Stope
authors.affiliation: Department of Biochemistry and Molecular Biology, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. antons.martincuks@rwth-aachen.de.
authors.forename: Antons
authors.initials: A
authors.lastname: Martincuks
authors.affiliation: Institute for Laboratory Animal Science, University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany. mvogt@ukaachen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Vogt
authors.affiliation: Department of Biochemistry and Molecular Biology, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. dgoertz@ukaachen.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Görtz
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, 10126, Turin, Italy. Annalisa.camporeale@unito.it.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Camporeale
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, 10126, Turin, Italy. valeria.poli@unito.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.affiliation: Department of Biochemistry and Molecular Biology, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. mueller-newen@rwth-aachen.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. tbruemmendorf@ukaachen.de.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. pziegler@ukaachen.de.|Institute for Occupational and Social Medicine, Aachen University, Aachen, Germany. pziegler@ukaachen.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ziegler
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse