Lnk deficiency partially mitigates hematopoietic stem cell aging
Alexey Bersenev
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Equal contribution.
Search for more papers by this authorKrasimira Rozenova
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Equal contribution.
Search for more papers by this authorJoanna Balcerek
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Equal contribution.
Search for more papers by this authorJing Jiang
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Search for more papers by this authorChao Wu
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Search for more papers by this authorWei Tong
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Search for more papers by this authorAlexey Bersenev
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Equal contribution.
Search for more papers by this authorKrasimira Rozenova
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Equal contribution.
Search for more papers by this authorJoanna Balcerek
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Equal contribution.
Search for more papers by this authorJing Jiang
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Search for more papers by this authorChao Wu
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Search for more papers by this authorWei Tong
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA
Search for more papers by this authorSummary
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.
Supporting Information
Fig. S1. Lineage reconstitution of serial transplanted mice.
Fig. S2. Determination of donor-derived HSCs in serial transplanted mice.
Table S1. Similarities aged Lnk-/- HSCs compared with young Lnk-/- HSCs and aged WT HSCs with young WT HSCs.
Table S2. Aged Lnk-/- HSCs show depletion of cell cycle and DNA repair pathways compared to aged WT HSCs.
Table S3. Young Lnk-/- HSCs show enrichment in anabolic signaling and metabolism compared to young WT HSCs.
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| acel862_sm_FigS1-2.pdf3.5 MB | Supporting info item |
| acel862_sm_TableS1.pdf105 KB | Supporting info item |
| acel862_sm_TableS2.pdf90.1 KB | Supporting info item |
| acel862_sm_TableS3.pdf91 KB | Supporting info item |
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