DISTINCT AND OVERLAPPING DIRECT EFFECTS OF MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA AND TRANSFORMING GROWTH-FACTOR-BETA ON HEMATOPOIETIC PROGENITOR STEM-CELL GROWTH

Both transforming growth factor P (TGF beta) and macrophage inflammato ry protein 1 alpha (MIP-1 alpha) have been shown to be multifunctional regulators of hematopoiesis that can either inhibit or enhance the gr owth of hematopoietic progenitor cells (HPC). We report here the spect rum of activities of these two cytokines on different hematopoietic pr ogenitor and stem cell populations, and whether these effects are dire ct or indirect. MIP-1 alpha enhances interleukin-3 (IL-3)/ and granulo cyte-macrophage colony-stimulating factor (GM-CSF)/induced colony form ation of normal bone marrow progenitor cells (BMC) and lineage-negativ e (Lin(-)) progenitors, but has no effect on G-CSF or CSF-1/induced co lony formation. Similarly, TGF beta enhances GM-CSF/induced colony for mation of normal BMC and Lin(-) progenitors. In contrast; TGF beta inh ibits IL-3/ and CSF-1/induced colony formation of Lin(-) progenitors. The effects of MIP-1 alpha and TGF beta on the growth of Lin(-) progen itors were direct and correlate with colony formation in soft agar. Se paration of the Lin(-) cells into Thy-1 and Thy-1(lo) subsets showed t hat the growth of Thy-1(lo) Lin(-) cells is directly inhibited by MIP- 1 alpha and TGF beta regardless of the cytokine used to stimulate grow th (IL-3, GM-CSF, or CSF-1). In contrast, two other stem cell populati ons (0% to 15% Hoechst 33342/Rhodamine 123 [Ho/Rh123] and Lin(-)Sca-1( +) cells) were markedly inhibited by TGF beta and unaffected by MIP-1 alpha. Furthermore, MIP-1 alpha has no effect on high proliferative po tential colony-forming cells 1 or 2 (HPP-CFC/1 or /2) colony formation in vitro, whereas TGF beta inhibits both HPP-CFC/1 and HPP-CFC/2. Thu s, MIP-1 alpha and TGF beta are direct bidirectional regulators of HPC growth, whose effects are dependent on other growth factors present a s well as the maturational state of the HPC assayed. The spectrum of t heir inhibitory and enhancing activities shows overlapping yet distinc t effects. (C) 1994 by The American Society of Hematology.