Megakaryocyte TGFβ1 partitions erythropoiesis into immature progenitor/stem cells and maturing precursors
- 26 August 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 136 (9), 1044-1054
- https://doi.org/10.1182/blood.2019003276
Abstract
Erythropoietin (EPO) provides the major survival signal to maturing erythroid precursors (EPs) and is essential for terminal erythropoiesis. Nonetheless, progenitor cells can irreversibly commit to an erythroid fate well before EPO acts, risking inefficiency if these progenitors are unneeded to maintain red blood cell (RBC) counts. We identified a new modular organization of erythropoiesis and, for the first time, demonstrate that the pre-EPO module is coupled to late EPO-dependent erythropoiesis by megakaryocyte (Mk) signals. Disrupting megakaryocytic transforming growth factor beta 1 (Tgfb1) disorganized hematopoiesis by expanding the pre-EPO pool of progenitor cells and consequently triggering significant apoptosis of EPO-dependent EPs. Similarly, pharmacologic blockade of TGF beta signaling in normal mice boosted the pre-EPO module, leading to apoptosis of EPO-sensitive EPs. Subsequent treatment with low-dose EPO triggered robust RBC production in both models. This work reveals modular regulation of erythropoiesis and offers a new strategy for overcoming chronic anemias.This publication has 43 references indexed in Scilit:
- Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblastsHaematologica, 2013
- From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modificationsBlood, 2011
- Gene induction and repression during terminal erythropoiesis are mediated by distinct epigenetic changesBlood, 2011
- Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesisProceedings of the National Academy of Sciences of the United States of America, 2009
- Erythropoiesis stimulating agents have limited therapeutic activity in transfusion‐dependent patients with primary myelofibrosis regardless of serum erythropoietin levelEuropean Journal of Haematology, 2009
- Generation of mice with a conditional allele for transforming growth factor beta 1 genegenesis, 2009
- Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDSBlood, 2008
- Elucidation of the Phenotypic, Functional, and Molecular Topography of a Myeloerythroid Progenitor Cell HierarchyCell Stem Cell, 2007
- Transforming Growth Factor : A Central Modulator of Pulmonary and Airway Inflammation and FibrosisProceedings of the American Thoracic Society, 2006
- Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in miceBlood, 2002