IDENTIFICATION AND CHARACTERIZATION OF AN INHIBITOR OF HEMATOPOIETIC STEM-CELL PROLIFERATION

The haemopoietic system has three main compartments: multi-potential stem cells, intermediate stage progenitor cells and mature cells. The availability of simple reproducible culture systems1 has made possible the characterization and purification of regulators of the progenitor cells, including colony-stimulating factors and interleukins. In contrast, our knowledge of the regulators involved in the control of stem cell proliferation is limited. The steady-state quiescent status of the haemopoietic stem cell compartment is thought to be controlled by locally acting regulatory elements present in the stromal microenvironment2, but their purification has been hampered by the lack of suitable culture systems. We have recently developed a novel in vitro colony assay that detects a primitive cell (CPU-A) 3 which has similar proliferative charac-teristics, in normal and regenerating bone marrow, to the CFU-S (haemopoietic stem cells, as defined by the spleen colony assay4) and which responds to CFU-S-specific proliferation regulators. We have now used this assay to purify to homogeneity a macrophage-derived reversible inhibitor of haemopoietic stem cell proliferation (stem cell inhibitor, SCI). Antibody inhibition and sequence data indicate that SCI is identical to a previously described cytokine, macrophage inflammatory protein-lα ( MIP-lα), and that SCI/MIP-lα is functionally and antigenically iden-tical to the CFU-S inhibitory activity obtained from primary cultures of normal bone marrow cells5. The biological activities of SCI/MIP-lα suggest that it is a primary negative regulator of stem cell proliferation and that it has important therapeutic appli-cations in protecting haemopoietic stem cells from damage during cytotoxic therapies for cancer. ö © 1990 Nature Publishing Group.