Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

• Novella Guidi ^[6] ; Mehmet Sacma ^[6] ; Ludger Ständker ^[2] ; Karin Soller ^[6] ; Gina Marka ^[6] ; Karina Eiwen ^[6] ; Johannes M Weiss ^[3] ; Frank Kirchhoff ^[4] ; Tanja Weil ^[5] ; Jose A Cancelas ^[1] ; Maria Carolina Florian ^[6] ; Hartmut Geiger ^[7]
  1. [1] Cincinnati Children's Hospital Medical Center

     Cincinnati Children's Hospital Medical Center

     City of Cincinnati, Estados Unidos

     
  2. [2] University of Ulm

     University of Ulm

     Stadtkreis Ulm, Alemania

     
  3. [3] University Hospital Ulm

     University Hospital Ulm

     Stadtkreis Ulm, Alemania

     
  4. [4] 4 Institute of Molecular Virology Universitätsklinikum Ulm Ulm Germany
  5. [5] 5 Institute of Organic Chemistry III University of Ulm Ulm Germany
  6. [6] 1 Institute of Molecular Medicine and Aging Research Center Ulm University of Ulm Ulm Germany
  7. [7] 1 Institute of Molecular Medicine and Aging Research Center Ulm University of Ulm Ulm Germany; 6 Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center Cincinnati OH USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 7, 2017, págs. 840-853
• Idioma: inglés
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  • 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.