• Open Access

Lnk deficiency partially mitigates hematopoietic stem cell aging

Authors

  • Alexey Bersenev,

    1. Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
    2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
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    • Equal contribution.

  • Krasimira Rozenova,

    1. Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
    2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
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    • Equal contribution.

  • Joanna Balcerek,

    1. Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
    2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
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    • Equal contribution.

  • Jing Jiang,

    1. Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
    2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
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  • Chao Wu,

    1. Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
    2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
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  • Wei Tong

    1. Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
    2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
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Wei Tong, Children’s Hospital of Philadelphia, Abramson Bldg, Suite 316A, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA. Tel.: 267 426 0930; fax: 267 426 5476; e-mail: tongw@email.chop.edu

Summary

Upon aging, the number of hematopoietic stem cells (HSCs) in the bone marrow increases while their repopulation potential declines. Moreover, aged HSCs exhibit lineage bias in reconstitution experiments with an inclination toward myeloid at the expense of lymphoid potential. The adaptor protein Lnk is an important negative regulator of HSC homeostasis, as Lnk deficiency is associated with a 10-fold increase in HSC numbers in young mice. However, the age-related increase in functional HSC numbers found in wild-type HSCs was not observed in Lnk-deficient animals. Importantly, HSCs from aged Lnk null mice possess greatly enhanced self-renewal capacity and diminished exhaustion, as evidenced by serial transplant experiments. In addition, Lnk deficiency ameliorates the aging-associated lineage bias. Transcriptome analysis revealed that WT and Lnk-deficient HSCs share many aging-related changes in gene expression patterns. Nonetheless, Lnk null HSCs displayed altered expression of components in select signaling pathways with potential involvement in HSC self-renewal and aging. Taken together, these results suggest that loss of Lnk partially mitigates age-related HSC alterations.

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