Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells

被引:103
作者
Guidi, Novella [1 ,2 ]
Sacma, Mehmet [1 ,2 ]
Staendker, Ludger [3 ]
Soller, Karin [1 ,2 ]
Marka, Gina [1 ,2 ]
Eiwen, Karina [1 ,2 ]
Weiss, Johannes M. [4 ]
Kirchhoff, Frank [5 ]
Weil, Tanja [6 ]
Cancelas, Jose A. [7 ]
Florian, Maria Carolina [1 ,2 ]
Geiger, Hartmut [1 ,2 ,7 ]
机构
[1] Univ Ulm, Inst Mol Med, Ulm, Germany
[2] Univ Ulm, Aging Res Ctr Ulm, Ulm, Germany
[3] Univ Ulm, Kompetenzzentrum Ulm Peptide Pharmaceut, Ulm, Germany
[4] Univ Klinikum Ulm, Dept Dermatol & Allerg Dis, Ulm, Germany
[5] Univ Klinikum Ulm, Inst Mol Virol, Ulm, Germany
[6] Univ Ulm, Inst Organ Chem 3, Ulm, Germany
[7] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA
关键词
aging; hematopoietic stem cell; microenvironment; niche; osteopontin; BONE-MARROW NICHE; PROGENITOR CELLS; STROMAL CELLS; MICE; REGENERATION; MICROENVIRONMENT; ALPHA(9)BETA(1); LOCALIZATION; REQUIREMENTS; COMPONENT;
D O I
10.15252/embj.201694969
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:840 / 853
页数:14
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