Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System
Burak H. Yalcin,
Jadranka Macas,
Eliza Wiercinska,
Patrick N. Harter,
Malak Fawaz,
Tessa Schmachtel,
Ilaria Ghiro,
Ewa Bieniek,
Djuro Kosanovic,
Sonja Thom,
Marcus Fruttiger,
Makoto M. Taketo,
Ralph T. Schermuly,
Michael A. Rieger,
Karl H. Plate,
Halvard Bonig,
Stefan Liebner
Affiliations
Burak H. Yalcin
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Jadranka Macas
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Eliza Wiercinska
Institute for Transfusion Medicine and Immunohaematology, and DRK-Blutspendedienst BaWüHe, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
Patrick N. Harter
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Malak Fawaz
Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Tessa Schmachtel
Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Ilaria Ghiro
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Ewa Bieniek
German Center for Lung Research (DZL), Department of Internal Medicine, Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany
Djuro Kosanovic
German Center for Lung Research (DZL), Department of Internal Medicine, Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany
Sonja Thom
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Marcus Fruttiger
UCL Institute of Ophthalmology, London EC1V 9EL, UK
Makoto M. Taketo
Kyoto University Hospital-iACT Graduate School of Medicine, Kyoto University, Kyoto 06-8501, Japan
Ralph T. Schermuly
German Center for Lung Research (DZL), Department of Internal Medicine, Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany
Michael A. Rieger
Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Karl H. Plate
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
Halvard Bonig
Institute for Transfusion Medicine and Immunohaematology, and DRK-Blutspendedienst BaWüHe, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
Stefan Liebner
Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
The bone marrow (BM) hematopoietic system (HS) gives rise to blood cells originating from hematopoietic stem cells (HSCs), including megakaryocytes (MKs) and red blood cells (erythrocytes; RBCs). Many steps of the cell-fate decision remain to be elucidated, being important for cancer treatment. To explore the role of Wnt/β-catenin for MK and RBC differentiation, we activated β-catenin signaling in platelet-derived growth factor b (Pdgfb)-expressing cells of the HS using a Cre-lox approach (Ctnnb1BM-GOF). FACS analysis revealed that Pdgfb is mainly expressed by megakaryocytic progenitors (MKPs), MKs and platelets. Recombination resulted in a lethal phenotype in mutants (Ctnnb1BM-GOFwt/fl, Ctnnb1BM-GOFfl/fl) 3 weeks after tamoxifen injection, showing an increase in MKs in the BM and spleen, but no pronounced anemia despite reduced erythrocyte counts. BM transplantation (BMT) of Ctnnb1BM-GOF BM into lethally irradiated wildtype recipients (BMT-Ctnnb1BM-GOF) confirmed the megakaryocytic, but not the lethal phenotype. CFU-MK assays in vitro with BM cells of Ctnnb1BM-GOF mice supported MK skewing at the expense of erythroid colonies. Molecularly, the runt-related transcription factor 1 (RUNX1) mRNA, known to suppress erythropoiesis, was upregulated in Ctnnb1BM-GOF BM cells. In conclusion, β-catenin activation plays a key role in cell-fate decision favoring MK development at the expense of erythroid production.
