TGF-BETA AND MIP-1-ALPHA EXERT THEIR MAIN INHIBITORY ACTIVITY ON VERYPRIMITIVE CD34(-) CELLS BUT SHOW OPPOSITE EFFECTS ON MORE MATURE CD34(+)CD38(+) HUMAN HEMATOPOIETIC PROGENITORS(+)CD38()

We investigated the effects of transforming growth factor-beta (TGF-be ta) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) on very primitive CD34(++)CD38(-) and on more mature CD34(+)CD38(+) human hema topoietic progenitor cells by means of a two stage pre-colony-forming cell (pre-CFC) assay. The first (liquid) stage of this assay allows ev aluation of the effects of TGF-beta and MIP-1 alpha on the ''primary'' proliferation of the progenitors under study and on the generation of ''secondary'' colony-forming cells (CFC, cells for which a second sta ge semisolid clonogenic assay was used as a read-out). TGF beta inhibi ted the proliferation and CFC generation of CD34(++)CD38(-) and CD34()CD38(+) cells, showing the strongest inhibitory activity on CD34(++)C D38(-) cells. MIP-1 alpha exerted a weaker inhibitory activity on CD34 (++)CD38(-) cells, whereas it enhanced the primary proliferation of CD 34(+)CD38(+) cells and generation of secondary CFC in this subpopulati on. Thus, TGF-beta and MIP-1 alpha both inhibit very primitive CD34(+)CD38(-) cells, but they are not equally potent. The effects of TGF-be ta and MIP-1 alpha on more mature progenitor cells are more complex. O ur results and data from the literature indicate that, as progenitor c ells mature, they reach a ''pivotal point'' at a certain stage in thei r differentiation pathway, depending on the inhibitor, where they are no longer inhibited or where they may even be stimulated by the former inhibitor to proliferate.