RELATIVE TO ADULT MARROW, FETAL LIVER REPOPULATES NEARLY 5 TIMES MOREEFFECTIVELY LONG-TERM THAN SHORT-TERM

Multilineage precursor cells from 14-day B6 (C57B1/6J) mouse fetal liv er and adult bone marrow that repopulate both the lymphoid and myeloid systems were compared by competitive repopulation. Cells were assayed in normally functioning populations, and enrichment, tissue culture, and induced marking were avoided since these manipulations might affec t cell function. Fetal or adult donor cells were mixed with marked adu lt competitor cells and transplanted into irradiated recipients whose blood was tested at short (25-33-day) or long (105-245-day) time perio ds after transplantation. Proportions of lymphocytes, granulocytes, an d platelets descended from donor precursors were measured by GPI (gluc osephosphate isomerase) isozyme genetic markers in congenic mice, and represent the repopulating abilities of these precursors relative to t he standard competitor. For short-term repopulation 25-33 days after t ransplantation, fetal and adult donor cells were similar; in three stu dies, fetal liver contributed 0.8, 1.1, and 1.4 times as much as adult marrow per 10(5) cells transplanted. However, when long-term (105-245 -day) repopulation was tested in the same recipients, fetal liver cont ributed 3.5, 5.0, and 7.1 times as much as adult marrow. Ratios of lon g-term/short-term repopulating abilities in fetal liver relative to st andard adult marrow competitors were 2.5, 8.9, and 4.7, while in marro w controls, these ratios remained approximately one (1.14 and 0.80). T hus, 14-day fetal liver contains several times more long-term repopula ting cells relative to short-term repopulating cells than does adult m arrow. Ratios of long-term/short-term fetal cells were unchanged by pr ecursor enrichment. The AA4.1(+), Ly-GA/E+, lineage low fraction had a ratio of 4.4, although it repopulated 276 times better than unenriche d fetal cells whose ratio was 4.7. There are two hypotheses that expla in these data most simply: 1) There may be only a single multilineage precursor, but after transplantation cells seed in different microenvi ronments that support either long-term or short-term function. 2) Conv ersely, the difference may be at the stem cell level rather than the m icroenvironmental level, so that there are two types of stem cells wit h multilineage differentiating ability, but only one functions over th e long-term. The current report defines new conditions required by eac h hypothesis. If functional life spans are defined by seeding sites, a s in hypothesis 1, fetal cells seed much higher proportions of long-te rm sites than adult cells. If different types of stem cells function s hort-term and long-term, as in hypothesis 2, they are not distinguishe d by markers allowing a 276-fold enrichment to 1367 times the repopula ting ability of fresh marrow.