A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche
| Autor: | Kilian Sottoriva, Karol Palasiewicz, James Hyun, Xiaopei Gao, Henar Cuervo, Sweta S. Soni, Na Yoon Paik, Asrar B. Malik, Kostandin V. Pajcini, Lijian Shao, Jalees Rehman, Jizhou Zhang, Daniel Lucas |
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| Rok vydání: | 2019 |
| Předmět: |
Pancytopenia
Mutant Notch signaling pathway Biology Mice 03 medical and health sciences 0302 clinical medicine Bone Marrow Mutant protein medicine Animals Humans Regeneration Receptor Notch1 HES1 Mice Knockout Gene Expression Profiling Wild type Endothelial Cells Hematology Hematopoietic Stem Cells Receptor TIE-2 Phenotype Cell biology Haematopoiesis Editorial medicine.anatomical_structure Cellular Microenvironment Gene Expression Regulation Gamma Rays embryonic structures Fluorouracil Bone marrow Signal Transduction 030215 immunology |
| Zdroj: | Haematologica. 104:2164-2177 |
| ISSN: | 1592-8721 0390-6078 |
| Popis: | Loss-of-function studies have determined that Notch signaling is essential for hematopoietic and endothelial development. By deleting a single allele of the Notch1 transcriptional activation domain we generated viable, post-natal mice exhibiting hypomorphic Notch signaling. These heterozygous mice, which lack only one copy of the transcriptional activation domain, appear normal and have no endothelial or hematopoietic phenotype, apart from an inherent, cell-autonomous defect in T-cell lineage development. Following chemotherapy, these hypomorphs exhibited severe pancytopenia, weight loss and morbidity. This phenotype was confirmed in an endothelial-specific, loss-of-function Notch1 model system. Ang1, secreted by hematopoietic progenitors after damage, activated endothelial Tie2 signaling, which in turn enhanced expression of Notch ligands and potentiated Notch1 receptor activation. In our heterozygous, hypomorphic model system, the mutant protein that lacks the Notch1 transcriptional activation domain accumulated in endothelial cells and interfered with optimal activity of the wildtype Notch1 transcriptional complex. Failure of the hypomorphic mutant to efficiently drive transcription of key gene targets such as Hes1 and Myc prolonged apoptosis and limited regeneration of the bone marrow niche. Thus, basal Notch1 signaling is sufficient for niche development, but robust Notch activity is required for regeneration of the bone marrow endothelial niche and hematopoietic recovery. |
| Databáze: | OpenAIRE |
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