Genetic regulation of hematopoietic stem cell exhaustion during development and growth.

OBJECTIVE: During aging, hematopoietic stem cell (HSC) exhaustion is more severe in BALB/cByJ (BALB) mice than in C57BL/6J (B6) mice. Our objective is to determine whether HSC exhaustion during development from fetus to adult also is more severe for BALB than for B6 mice. MATERIALS AND METHODS: Hematopoietic stem cells from fetal liver cells (FLCs) and from young adult bone marrow cells (BMCs) were compared using the competitive repopulation assay to measure long-term repopulating ability (LTRA) and HSC expansion after serial transplantation. LTRAs were measured in repopulating units (RU), as the ability to produce donor-type erythrocytes and lymphocytes in lethally irradiated recipients relative to the congenic fresh marrow competitor. To test expansion, FLCs or BMCs were serially transplanted into lethally irradiated carriers whose marrow cells were compared using fluorescence-activated cell staining (FACS), and subsequently tested for LTRA. RESULTS: BALB and B6 FLCs, respectively, repopulated 2.6 and 13.5 times as well as BMCs. LTRAs correlated with HSC expansion for BALB, but not B6. Per million donor cells, CD34(-) HSC-enriched fractions (HEFs) and total RU values were 6.8 and 4.6 times higher for FLCs than for BMCs in BALB carriers, while these ratios were only 1.2 and 0.97 higher in B6 carriers. CONCLUSION: In B6 HSC development, LTRA is dissociated from expansion. Although 1 x 10(6) BMCs have much lower LTRA, they expand HSCs as well as 1 x 10(6) FLCs. HSC expansion is partly exhausted in BALB, but not B6, during development