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EMBO J. 2017 Apr 3;36(7):840-853. doi: 10.15252/embj.201694969. Epub 2017 Mar 2.

Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

Author information

1
Institute of Molecular Medicine and Aging Research Center Ulm, University of Ulm, Ulm, Germany.
2
Kompetenzzentrum Ulm Peptide Pharmaceuticals, University of Ulm, Ulm, Germany.
3
Department of Dermatology and Allergic Diseases, Universitätsklinikum Ulm, Ulm, Germany.
4
Institute of Molecular Virology, Universitätsklinikum Ulm, Ulm, Germany.
5
Institute of Organic Chemistry III, University of Ulm, Ulm, Germany.
6
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
7
Institute of Molecular Medicine and Aging Research Center Ulm, University of Ulm, Ulm, Germany hartmut.geiger@uni-ulm.de.

Abstract

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging.

KEYWORDS:

aging; hematopoietic stem cell; microenvironment; niche; osteopontin

PMID:
28254837
PMCID:
PMC5376966
DOI:
10.15252/embj.201694969
[Indexed for MEDLINE]
Free PMC Article

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