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Despite the well-established cell-intrinsic role of epigenetic factors in normal and malignant hematopoiesis, their cell-extrinsic role remains largely unexplored. Herein we investigated the hematopoietic impact of inactivating Ezh2, a key component of polycomb repressive complex 2 (PRC2), in the fetal liver (FL) vascular niche. Hematopoietic specific (Vav-iCre) Ezh2 inactivation enhanced FL hematopoietic stem cell (HSC) expansion with normal FL erythropoiesis. In contrast, endothelium (Tie2-Cre) targeted Ezh2 inactivation resulted in embryonic lethality with severe anemia at embryonic day 13.5 despite normal emergence of functional HSCs. Ezh2-deficient FL endothelium overexpressed Mmp9, which cell-extrinsically depleted the membrane-bound form of Kit ligand (mKitL), an essential hematopoietic cytokine, in FL. Furthermore, Mmp9 inhibition in vitro restored mKitL expression along with the erythropoiesis supporting capacity of FL endothelial cells. These data establish that Ezh2 is intrinsically dispensable for FL HSCs and provides proof of principle that modulation of epigenetic regulators in niche components can exert a marked cell-extrinsic impact.

Original publication




Journal article



Publication Date





2223 - 2234


Anemia, Animals, Biomarkers, Cells, Cultured, Endothelial Cells, Enhancer of Zeste Homolog 2 Protein, Fetus, Fluorescent Antibody Technique, Gene Expression, Gene Silencing, Hematopoiesis, Extramedullary, Hematopoietic Stem Cells, Immunohistochemistry, Liver, Matrix Metalloproteinase 9, Mice, Phenotype, Receptor, TIE-2, Stem Cell Factor