Mitroulis, Ioannis, Chen, Lan-Sun, Singh, Rashim Pal et al. (21 more authors) (2017) Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. Journal of Clinical Investigation. pp. 3624-3639. ISSN 1558-8238
Abstract
Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details |
Keywords: | Animals,Carrier Proteins/genetics,Chemokine CXCL12/genetics,Endothelial Cells/metabolism,Hematopoietic Stem Cells/metabolism,Humans,Integrin beta3/genetics,Intercellular Signaling Peptides and Proteins,Mice,Mice, Knockout,Myelopoiesis,Stem Cell Niche,Stress, Physiological |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) |
Depositing User: | Pure (York) |
Date Deposited: | 21 Jan 2020 09:40 |
Last Modified: | 17 Dec 2024 00:15 |
Published Version: | https://doi.org/10.1172/JCI92571 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1172/JCI92571 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:155861 |
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