title: Thrombopoietin induces hematopoiesis from mouse ES cells via HIF-1α-dependent activation of a BMP4 autoregulatory loop.
abstract: Understanding the molecular mechanisms underlying hematopoietic differentiation of embryonic stem (ES) cells may help to ascertain the conditions for the in vitro generation of hematopoietic cells. Previously, we found that patients with congenital amegakaryocytic thrombocytopenia (CAMT), who develop pancytopenia early after birth, harbor mutations within the thrombopoietin (TPO) receptor, c-MPL. This knowledge, together with observations in vitro and in vivo, suggests that TPO/c-MPL signaling promotes early hematopoiesis. However, the mechanisms underlying TPO signaling are not fully elucidated. Here, we describe a direct connection between TPO and bone morphogenetic protein 4 (BMP4) signaling pathways in determining the hematopoietic fate of ES cells. Morphogen BMP4 is known to induce early hematopoietic differentiation of ES cells. Treatment of ES cells with TPO induced the autocrine production of BMP4 with concomitant upregulation of the BMP receptor BMPR1A, phosphorylation of SMAD1, 5, 8, and activation of specific BMP4 target genes; this was mediated by TPO-dependent binding of transcription factor HIF-1α to the BMP4 gene promoter. Treatment of ES cells with the BMP antagonist noggin substantially reduced TPO-dependent hematopoietic differentiation of ES cells. Thus, our findings contribute to the establishment of techniques for generating hematopoietic cells from ES cells.
authors.affiliation: Stem Cell and Tissue Engineering Research Center, Faculty of Medicine, University of Pembangunan Nasional "Veteran,", Jakarta, Indonesia.
authors.forename: Andri
authors.initials: A
authors.lastname: Pramono
authors.affiliation: Departments of Hematology, Oncology, Immunology, Rheumatology, and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Zahabi
authors.affiliation: Departments of Hematology, Oncology, Immunology, Rheumatology, and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morishima
authors.affiliation: Pediatric Department of the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lan
authors.affiliation: Department of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.affiliation: Departments of Hematology, Oncology, Immunology, Rheumatology, and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
mesh_terms: D000818:Animals; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D058732:Embryoid Bodies / Q000166:cytology; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013926:Thrombopoietin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055415:Bone Morphogenetic Protein 4; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin
keywords: BMP4; ES cells; HIF-1α; hematopoiesis; thrombopoietin