Increased Stem Cell Mobilization Proficiency in Aged Mice.

Abstract

The ability of healthy, older individuals to undergo stem cell mobilization in response to granulocyte colony-stimulating factor (G-CSF) has not been specifically investigated. Aging is usually associated with an overall decline in tissue and cellular function. Therefore it is anticipated that the ability to mobilize stem cells in response to G-CSF may be reduced in aged individuals, although whether or not a negative correlation exists between age and mobilization is still under debate. We analyzed the influence of aging on the mobilization proficiency in healthy mice. Young 2–3 month old and aged 20–26 month old, which corresponds to a human age of 70, were mobilized according to standard procedures. The frequency of hematopoietic progenitor cells in peripheral blood (PB) of aged mice was 3- fold elevated over the frequency found in PB of young mice. The aged animals possessed the ability to mobilize increased numbers of primitive hematopoietic cells despite a slight, but significant anemia. This 3-fold difference in stem cell frequency in PB was further confirmed by long-term transplantation experiments. To determine if the increased ability to mobilize is intrinsic to aged hematopoietic stem cells or driven by age-associated, extrinsic changes in the BM microenvironment, a competitive mobilization assay based on the Ly5.2/Ly5.1 mismatch system was used. The genetic origin of the CFCs was determined by flow cytometry. In this assay, as previously reported, aged BM HSCs contribute to only 30% chimerism in PB prior to mobilization, resulting in a 1:2 ratio in favor of young cells in PB chimerism 3 months post-transplant. In contrast, when we analyzed the CFC chimerism of the competitively transplanted animals post-mobilization, 85% of all CFC from PB were derived from cells from old mice, strongly arguing that increased mobilization proficiency is a) not a simple consequence of the increased CFC content in aged BM and b) to a large extent intrinsic to the aged primitive hematopoietic cell, and thus relatively independent from the aged BM microenvironment. These data also imply that the stroma stem cell/interaction might change with age.