The Effect of Aging on Hematopoietic Stem Cell Homing and Engraftment.

Abstract

The efficiency with which hematopoietic stem (HSC) and progenitor cells (HPC) home to bone marrow (BM) critically impacts their engraftment after transplantation. Little is known about the effects of aging on this parameter. The present study was thus initiated to test the hypothesis that homing efficiency of HSCs and HPCs to the BM will vary with aging of the donor, recipient, or both. Young or old C57BL/6 BM cells were intravenously injected into lethally irradiated old or young Ly-5 congenic recipient mice. Three or 24 hours later, the numbers of HPCs or HSCs that could be recovered from the BM and spleen were assayed using an in vitro colony-forming cell assay or an in vivo limiting-dilution competitive repopulating unit (CRU) assay and compared to the number of such cells that were initially transplanted. The frequency of CRU in old BM was two-fold higher than that in young BM (~1 per 10,000 vs. 24,000 cells). However, old CRU homed less efficiently to young BM after 24 hours than did young HSCs (3% vs. 10%). The proliferative potential of individual HSCs (measured as the overall level of engraftment in mice transplanted with 1 CRU) did not change with donor age, but was reduced by advanced recipient age, and was also reduced by prior transplantation as observed previously. HSC differentiation potential (defined by the proportion of lymphocytes and myeloid cells in mice transplanted with 1 CRU) was also skewed toward myelopoiesis at the expense of lymphopoiesis with both donor and recipient age. Donor and recipient aging exerted similar effects on the 3 hour BM and spleen seeding efficiency of HPCs, both leading to a 40% decrease in BM homing, and a 5-fold decrease in spleen homing compared with young HPCs transplanted into young recipients. In terms of the rate of hematopoietic engraftment, advanced recipient age resulted in slower erythrocyte and platelet recovery, but moderately accelerated leukocyte regeneration compared with young cells transplanted into young recipients. Conversely, old donor cells exhibited faster leukocyte and platelet recovery, but erythrocyte recovery was essentially unchanged compared to young donor cells. In sum, these data suggest that primitive hematopoietic cells undergo intrinsic aging-related changes in homing efficiency, proliferation/differentiation potential, and engraftment capability that are also extrinsically affected by an older BM microenvironment. These findings have important implications for clinical stem cell transplantation where older individuals often serve as donors for elderly patients.