Genetic regulation of HSC exhaustion during development and aging
Genetic regulation of HSC exhaustion during development and agingWe have shown that HSC functionality declines much more with age in BALB/cByJ (BALB) and DBA/2J (D2) mice than in C57BL/6J (B6) mice. The measure that best showed genetic regulation of HSC aging was the repopulating ability of HSCs, in vivo, in serially transplanted carriers. This measures loss of HSC expansion. Comparing HSCs from young adult and aged donors in irradiated carriers, the repopulating ability of HSCs from BALB mice declined about 4-fold with age, while the repopulating ability in B6 mice declined only 0.4-fold (Chen et al., 2000a). Now we are testing mechanisms of genetic regulation and searching for the candidate genes responsible.
Genetic regulatory patterns of HSC exhaustion during development emerge when HSCs expand in a serially transplanted carrier. The expansion ability of HSCs from fetal vs. adult BALB/cByJ (BALB) mice declines about 4-fold. In sharp contrast, the expansion of HSCs from both fetal and adult C57BL/6J (B6) mice are equally functional, despite a large advantage of the fetal HSCs in competitive repopulation (Yuan et al., 2005). The dissociation of expansion in HSCs from fetal and adult B6 mice suggests that a previously unknown primitive precursor is responsible for repopulation in carriers. These possibilities are distinguished by limiting dilution in serial carriers.