Intrinsic and Microenvironmental Defects Are Involved in the Age-Related Changes of Lin − c-kit + Hematopoietic Progenitor Cells

The aim of this study was to evaluate through cross-transplantation models the effect of aging on the number of Lin⁻c-kit⁺ hematopoietic progenitor cells, on their ability to differentiate towards a lymphocyte phenotype, and on the role of the microenvironment in hematopoietic differentiation. The absolute number of purified Lin⁻c-kit⁺ cells from bone marrow was significantly lower in aged than in young mice. When transplanted in young recipients, Lin⁻c-kit⁺ hematopoietic progenitor cells from aged mice showed a reduced differentiation capacity in T cells and NK cells, compared to Lin⁻c-kit⁺ cells from young animals. The role of microenvironment in Lin⁻c-kit⁺ hematopoietic progenitor cells differentiation was evaluated by injecting young Lin⁻c-kit⁺ cells in young or aged recipients, the latter transplanted or not with a young thymus. In these conditions, the differentiation of Lin⁻c-kit⁺ cells from young mice in T and NK cells was less efficient in aged than in young recipients, independently of thymus grafting in aged recipients. In addition to quantitative defects qualitative alterations were also present in Lin⁻c-kit⁺ cells from aged mice, as evidenced by the fact that the injection of Lin⁻c-kit⁺ cells from aged donors in young recipients differentiated in CD4⁺ T cells that retained an interleukin-4 (IL-4) production in-between young and old control values. In conclusion, we have demonstrated that aging is associated with numerical and functional alterations of Lin⁻c-kit⁺ hematopoietic progenitor cells as well as with an altered microenvironment that is required for Lin⁻c-kit⁺ cells differentiation toward a lymphocyte phenotype.