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- Title
Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System.
- Authors
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; Liebner, Stefan
- 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 (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.
- Subjects
HEMATOPOIETIC system; BLOOD cells; RUNX proteins; PLATELET-derived growth factor; HEMATOPOIETIC stem cells; WNT signal transduction; ERYTHROCYTES; BONE marrow
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 23, p2765
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12232765