Cell-extrinsic hematopoietic impact of Ezh2 inactivation in fetal liver endothelial cells
| Autor: | Emanuele Azzoni, Sten Eirik W. Jacobsen, Paul Delgado-Olguin, Christopher A.G. Booth, Lijun Chi, Marella F. T. R. de Bruijn, Adam J. Mead, Wen Hao Neo |
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| Přispěvatelé: | Neo, W, Booth, C, Azzoni, E, Chi, L, Delgado-Olguín, P, de Bruijn, M, Jacobsen, S, Mead, A |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Endothelium Cell Immunology Fluorescent Antibody Technique Gene Expression Stem cell factor macromolecular substances Biology Biochemistry Article 03 medical and health sciences Mice Fetus medicine Animals Enhancer of Zeste Homolog 2 Protein Gene Silencing Cells Cultured Stem Cell Factor EZH2 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell Endothelial Cells Anemia Hematology Cell Biology Hematopoietic Stem Cells Embryonic stem cell Immunohistochemistry Receptor TIE-2 Cell biology Haematopoiesis 030104 developmental biology medicine.anatomical_structure Phenotype Matrix Metalloproteinase 9 Liver Hematopoiesis Extramedullary Erythropoiesis Biomarkers |
| Zdroj: | Blood. 131(20) |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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