Enhanced Cytokine Responsiveness Counteracts Age-Induced Decline in Hematopoietic Stem Cell Function

Abstract 2342

In recent years, it has become increasingly clear that physiologic aging has several profound cell intrinsic effects on hematopoietic stem cell (HSC) aging. This includes an altered output of mature progeny and an expansion of the HSC pool, although the latter is accompanied with several functional shortcomings. Because of the hierarchical structure of hematopoiesis, improving HSC function should present a promising avenue to restore aberrant hematopoietic function.

The signal adaptor protein Lnk, a relay of cytokine signaling, has been shown to negatively regulate hematopoiesis at several cellular stages. As a consequence of Lnk deficiency, mice display increased B lymphopoiesis and increased HSC numbers. The increase in HSC numbers has been suggested to arise by an increased ability of HSCs to self-renew. However, it has remained unclear how the enhanced sensitivity to cytokine signaling would affect hematopoiesis upon physiological age. In the present study, we investigated the effects of physiological aging on hematopoiesis in the Lnk^−/− mice. Aged wild-type mice showed a number of age-related alterations in the hematopoietic system including; increased HSC numbers, decreased lymphopoiesis and decreased reconstitution potential upon competitive transplantation. Most of these parameters were dramatically altered as a consequence of Lnk deficiency. When competitively transplanted, aged Lnk^−/− HSCs displayed a dramatically increased overall reconstitution potential compared to WT mice. Increases in reconstitution potential were observed in both primary and serially reconstituted recipient animals. Upon physiologic age, the lineage distribution of transplanted aged wild-type HSCs is skewed towards the myeloid lineage. By contrast, transplanted aged Lnk^−/− HSCs gave rise to a hematopoietic system with a balanced lineage distribution resembling that generated by young wild-type HSCs. The enhanced HSC potential of aged Lnk^−/− mice was uncoupled from effects on telomere length maintenance but displayed a distinct molecular profile in whole genome expression analysis. In summary, we demonstrate that deficiency of the signal adaptor molecule Lnk appears to functionally protect HSCs from many of the consequences of physiologic age, which at a broader level perhaps suggest a potential of cytokines to counteract age-related HSC decline.