Genetic regulation of primitive hematopoietic stem cell senescence

Objective. To define effects of strain on PHSC (primitive hematopoietic ste m cells) senescence (decline in function with age) in vivo, and to map a lo cus that regulates PHSC senescence. Materials and Methods. Long-term function and self-renewal were compared in bone marrow cells (BMC) from old and young mice of three strains: BALB/cBy (BALB), DBA/2 (D2) and C57BL/6 (B6), using competitive repopulation and se rial transplantation in vivo. BMC from each old or young donor were mixed w ith standard doses of congenic, genetically marked BMC and transplanted int o Lethally recipients. Percentages of donor-type erythrocytes and lymphocyt es in the recipients determined the functional ability of donor PHSC relati ve to the standard, where one repopulating unit (RU) of donor BMC equals th e repopulating ability of 100,000 standard competitor BMC. Using similar te chniques, repopulating abilities of old and young recombinant inbred (RI) d onors of 12 strains derived from BALB and B6 were compared in NK-depleted B ALBxB6 Fl recipients to map a locus that appears to have a major role in PH SC senescence, Results. PHSC function declined about 2 fold with age in BALB and D2 BR IC, and increased more than 2-fold with age in B6 BMC, with all old/young stra in differences significant, p < .01. Ten months after serial transplantatio n, young B6, BALB, and D2 PHSC had self-renewed 1.6-, 4.2-, and 3.2-fold be tter than old, with BALB and D2 old/young differences p < .01. Young B6 PHS C self-renewed 1.9- and 2.9-fold better than young BALB and D2 PHSC. The PH SC senescence phenotypes (old/young RU ratios) for 12 CS RI strains suggest ed a genetic linkage to D12Nyul7 on Chromosome 12, Conclusion. PHSC senescence is genetically regulated, and is much delayed i n the B6 strain compared to the BALE and D2 strains. A Lotus on Chromosome 12 may regulate PHSC senescence. (C) 2000 International Society for Experim ental Hematology. Published by Elsevier Science Inc.