ENHANCEMENT OF HUMAN HEMATOPOIESIS BY MAST-CELL GROWTH-FACTOR IN HUMAN-SHEEP CHIMERAS CREATED BY THE IN-UTERO TRANSPLANTATION OF HUMAN FETAL HEMATOPOIETIC-CELLS

We have previously described a unique model of long-term, multilineage , human hematopoietic chimerism in sheep created by the in utero trans plantation of human hematopoietic stem cells (HSC) into pre-immune fet al lambs. In this study, we examined the effect of chronic administrat ion of recombinant human mast cell growth factor (rhMGF) on 1) human c ell engraftment in pre-immune sheep and 2) human cell expression in hu man-sheep chimeras at 2-years posttransplant. rhMGF (25 mu g/kg) or sa line was administered in utero via chronic intraperitoneal (IP) cathet ers to three separate sets of twin fetuses on alternate days for 10 do ses following transplantation of human HSC. Flow-cytometric and karyot ype analyses of peripheral blood from two sets of twins at 45-days pos ttransplant and of peripheral blood from the remaining set of twins at birth revealed a significant increase in percentages of donor (human) progenitors and cells in rhMGF-treated lambs. rhMGF (60 mu g/kg/day) was also administered by IP injection to two, 2 year-old, human-sheep chimeras for 18 consecutive days. Flow-cytometric analysis of peripher al blood and bone marrow revealed a six- to seven-fold increase in hum an cell expression. The effect on early human progenitors (i.e., colon y-forming unit-mix [CFU-Mix], CFU granulocyte/macrophage [CFU-GM], and burst-forming unit-erythroid [BFU-E]) was determined by karyotype ana lysis of individual colonies grown under conditions favoring human cel l growth. A three- to five-fold increase in human CFU-Mix and BFU-E oc curred with a minimal increase in CFU-GM. This in vivo study supports in vitro data suggesting that MGF is a powerful regulator of human hem atopoiesis and preferentially stimulates early hematopoietic progenito rs. It also supports the potential value of the human-sheep model for the in vivo study of normal and abnormal human hematopoiesis.