Abstract
Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit(+) hematopoietic progenitors, megakaryocytes, and Leptin Receptor(+) (LepR(+)) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR(+) cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR(+) stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery.
Keywords:
Angiopoietin-1; developmental biology; hematopoietic; mouse; niche; regeneration; stem cell; stem cells; vascular.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-1 / genetics
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Angiopoietin-1 / metabolism*
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Animals
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Blood Vessels / cytology
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Blood Vessels / metabolism
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Blood Vessels / radiation effects
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism*
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Bone Marrow Cells / radiation effects
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Capillary Permeability / radiation effects
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Female
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Gamma Rays
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Gene Expression Regulation
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Hematopoiesis / genetics
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Hematopoiesis / radiation effects
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism*
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Hematopoietic Stem Cells / radiation effects
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Integrases / genetics
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Integrases / metabolism
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Male
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Megakaryocytes / cytology
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Megakaryocytes / metabolism
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Megakaryocytes / radiation effects
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Mice
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Mice, Transgenic
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Nestin / genetics
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Nestin / metabolism
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Osteoblasts / radiation effects
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Receptors, Leptin / genetics
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Receptors, Leptin / metabolism
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Regeneration / genetics*
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Regeneration / radiation effects
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Signal Transduction
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Stem Cell Niche / genetics*
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Stem Cell Niche / radiation effects
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Stromal Cells / cytology
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Stromal Cells / metabolism
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Stromal Cells / radiation effects
Substances
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Angiopoietin-1
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Angpt1 protein, mouse
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Nes protein, mouse
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Nestin
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Receptors, Leptin
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leptin receptor, mouse
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Proto-Oncogene Proteins c-kit
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Cre recombinase
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Integrases