Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function.
Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages. It has remained unclear how the enhanced sensitivity to cytokine signaling caused by LNK deficiency affects hematopoiesis upon aging. Our findings demonstrate that aged LNK-/- HSCs displayed a robust overall reconstitution potential and gave rise to a hematopoietic system with a balanced lineage distribution. Although aged LNK-/- HSCs displayed a distinct molecular profile in which reduced proliferation was central, little or no difference in the proliferation of aged LNK-/- HSCs was observed after transplantation when compared to aged WT HSCs. This coincided with equal telomere maintenance in WT and LNK-/- HSCs. Collectively, our studies suggest that enhanced cytokine signaling can counteract functional age-related HSC decline.
Lund University, Institution for Experimental Medical Science, Immunology section, BMC D14, Tornavägen 10, 221 84 Lund, Sweden.
Gudmundur L
GL
Norddahl
Martin
M
Wahlestedt
Santiago
S
Gisler
Mikael
M
Sigvardsson
David
D
Bryder
D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins