EARLY CD34(HIGH) CELLS CAN BE SEPARATED INTO KITHIGH CELLS IN WHICH TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) DOWN-MODULATES C-KIT AND KITLOW CELLS IN WHICH ANTI-TGF-BETA UPMODULATES C-KIT

We have previously shown that early human CD34(high) hematopoietic pro genitors are maintained quiescent in part through autocrine transformi ng growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in th e presence of interleukin-3, interleukin-6, granulocyte colony-stimula ting factor, and erythropoietin. TGF-beta 1 antisense oligonucleotides or anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor [SF]), which suggests that they control different pathways of regulation in these conditions. This finding also suggests that autocr ine TGF-beta 1 might suppress c-kit expression in primitive human hema topoietic progenitors. We have now distinguished two subpopulations of CD34(high) cells. One subpopulation expresses a c-kit mRNA that can b e downmodulated by exogenous TGF-beta 1 within 6 hours. Another subpop ulation of early CD34(high) cells expresses a low or undetectable leve l of c-kit mRNA, but its expression can beupmodulated within 6 hours b y anti-TGF-beta. These effects disappear 48 hours after induction and cannot be maintained longer than 72 hours, even if TGF-beta 1 or anti- TGF-beta serum are added every day. Similar kinetics, although delayed , are observed with KIT protein expression. On the contrary, no specif ic effect of TGF-beta 1 was observed on c-fms, GAPDH, and transferrin receptor gene expression in these early progenitors. These results cla rify the complex interaction between TGF-beta 1 and SF in normal early hematopoietic progenitors. SF does not switch off the TGF-beta 1 inhi bitory pathway. Autocrine TGF-beta 1 appears to maintain these cells i n a quiescent state, suppressing cell division by downmodulating the r eceptor of SF, a key cytokine costimulator of early progenitors. (C) 1 995 by The American Society of Hematology.