title: Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis.
abstract: Hyaluronan is the predominant glycosaminoglycan component of the extracellular matrix with an emerging role in hematopoiesis. Modulation of hyaluronan polymer size is responsible for its control over cellular functions, and the balance of hyaluronan synthesis and degradation determines its molecular size. Although two active somatic hyaluronidases are expressed in mammals, only deficiency in hyaluronidase-2 (Hyal-2) results in thrombocytopenia of unknown mechanism. Our results reveal that Hyal-2 knockout mice accumulate hyaluronan within their bone marrow and within megakaryocytes, the cells responsible for platelet generation. Proplatelet formation by Hyal-2 knockout megakaryocytes was disrupted because of abnormal formation of the demarcation membrane system, which was dilated and poorly developed. Importantly, peptide-mediated delivery of exogenous hyaluronidase rescued deficient proplatelet formation in murine and human megakaryocytes lacking Hyal-2. Together, our data uncover a previously unsuspected mechanism of how hyaluronan and Hyal-2 control platelet generation.
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Petrey
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Obery
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Kessler
authors.affiliation: Molecular Physiology Research Unit, Namur Research Institute for the Life Sciences, University of Namur, Namur, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Flamion
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. Electronic address: delamoc@ccf.org.
authors.forename: Carol A
authors.initials: CA
authors.lastname: de la Motte
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008533:Megakaryocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D060888:Real-Time Polymerase Chain Reaction; D034061:Thrombopoiesis / Q000502:physiology*
chemical_list: D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase