Gene array analysis of human hematopoietic stem cells reveals association between age, altered signaling and loss of lymphocyte potential

Aging of the hematopoietic system has widespread effects on all cellular components, including hematopoietic stem cells (HSCs) and lymphoid progenitors. Age-related defects in the HSC compartment can culminate in clinically relevant consequences, such as decreased function of adaptive immunity and increased incidence of myeloid diseases, including leukemia. In addition, difficulties associated with allogeneic hematopoietic cell transplantation for the treatment of malignant and non-malignant hematopoietic diseases may be compounded, since the risk of life-threatening complications is increased with prolonged periods of T-cell deficiency. The ability to promote T-cell generation from mobilized adult peripheral blood (PB) could provide improved immune reconstitution following transplantation, and as a result, improved patient outcomes. In the present study we examined the gene expression profiles of young and aged human HSCs from cord blood and adult mobilized PB, respectively, and found that Wnt signaling genes are differentially expressed in young and aged human HSCs, with less activation of Wnt signaling in aged HSCs. Utilizing OP9-DL1 co-culture to promote T-cell development under stable Notch signaling conditions, we found Wnt signaling is also important for T-lineage differentiation. Examination of Wnt signaling components and target gene activation in young and aged HSCs during T-differentiation revealed a correlation between reduced Wnt signal transduction, increasing age, and impaired or delayed T-cell differentiation. The defect in Wnt signal activation of aged HSCs appeared to occur in the early T-progenitor subset derived during in vitro differentiation. Our results reveal that reduced Wnt signaling activity may play a role in the age-related intrinsic defects of aged HSCs and early hematopoietic progenitors and suggest that manipulation of this pathway could contribute to improving T-cell generation and immune reconstitution.