ABILITY OF EARLY ACTING CYTOKINES TO DIRECTLY PROMOTE SURVIVAL AND SUPPRESS APOPTOSIS OF HUMAN PRIMITIVE CD34(-) BONE-MARROW CELLS WITH MULTILINEAGE POTENTIAL AT THE SINGLE-CELL LEVEL - KEY ROLE OF THROMBOPOIETIN()CD38()

Purified primitive progenitor/stem cells from bone marrow represent li kely target populations for ex vivo expansion of stem cells to be used in high-dose chemotherapy or gene therapy. Whereas such primitive pro genitor cells require combined stimulation by multiple cytokines for g rowth, some cytokines selectively promote viability rather than growth when acting individually. We investigated here for the first time the direct effects of cytokines on survival of primitive CD34(+)CD38(-) h uman bone marrow progenitor cells at the single-cell level, Interleuki n-3 (IL-3) and the ligands for c-kit (KL) and flt3 (FL) had direct and selective viability-promoting effects on a small fraction of CD34(+)C D38(-) but not CD34(+)CD38(+) progenitor cells. Interestingly, the rec ently cloned thrombopoietin (Tpo), although stimulating little growth, kept most CD34(+)CD38(-) progenitors viable after prolonged culture, maintaining twofold and fourfold more progenitors viable than KL and I L-3, respectively, A high fraction of these progenitors had a combined myeloid and erythroid differentiation potential, as well as capacity for prolonged production of progenitor cells under stroma-independent conditions. In addition, Tpo promoted viability of CD34(+)CD38(-) long -term culture-initiating cells, further supporting the idea that Tpo p romotes viability of primitive human progenitor cells, Finally, Tpo su ppressed apoptosis of CD34(+)CD38(-) cells in culture, Thus, the prese nt studies show a novel effect of Tpo, implicating a potential role of this cytokine in maintaining quiescent primitive human progenitor cel ls viable. (C) 1997 by The American Society of Hematology.