1. Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System.
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Yalcin, Burak H., Macas, Jadranka, Wiercinska, Eliza, Harter, Patrick N., Fawaz, Malak, Schmachtel, Tessa, Ghiro, Ilaria, Bieniek, Ewa, Kosanovic, Djuro, Thom, Sonja, Fruttiger, Marcus, Taketo, Makoto M., Schermuly, Ralph T., Rieger, Michael A., Plate, Karl H., Bonig, Halvard, and Liebner, Stefan
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HEMATOPOIETIC system ,BLOOD cells ,RUNX proteins ,PLATELET-derived growth factor ,HEMATOPOIETIC stem cells ,WNT signal transduction ,ERYTHROCYTES ,BONE marrow - Abstract
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 (Ctnnb1
BM-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. [ABSTRACT FROM AUTHOR]- Published
- 2023
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