INHIBITION OF PROLIFERATION AND INDUCTION OF DIFFERENTIATION OF PLURIPOTENT HUMAN EMBRYONAL CARCINOMA-CELLS BY OSTEOGENIC PROTEIN-1 (OR BONE MORPHOGENETIC PROTEIN-7)

BACKGROUND: Osteogenic protein-1 (OP-1) is a member of the transformin g growth factor-beta super family closely related to the bone morphoge netic proteins and also known as bone morphogenetic protein-7. Other m embers of this family of growth factors influence cell differentiation as well as cell growth in a number of systems. The Drosophila homolog encoded by the decapentaplegic locus is involved in dorsal-ventral pa ttern formation during embryogenesis, whereas the expression of severa l bone morphogenetic proteins including OP-1 is developmentally regula ted in mammalian embryos. EXPERIMENTAL DESIGN: The effect of recombina nt human OP-1 on the proliferation and differentiation of an establish ed pluripotent human embryonal carcinoma (EC) cell line, NTERA2, and t hree nullipotent human EC cell lines, 2102Ep, 833KE: and TERA-1, was i nvestigated. These cells were grown under reduced serum conditions, an d differentiation was monitored by morphology and expression of marker antigens. RESULTS: OP-1 inhibited proliferation of NTERA2 and induced their differentiation, marked by changes in cellular morphology, the loss of EC cell antigens (SSEA3, SSEA4, the liver isozyme of alkaline phosphatase), and the appearance of new antigens, notably SSEA1 and cl ass 1 major histocompatibility complex antigens. These changes were ir reversible and did not involve significant cell degeneration or cell d eath. The OP-1-induced differentiation of NTERA2 appeared distinct fro m that induced by either retinoic acid or hexamethylene bisacetamide. Nevertheless, OP-1 did induce the homeobox gene, HOXA1. By contrast, O P-1 elicited only a limited and partial response from the nullipotent EC cell lines. CONCLUSIONS: Our results suggest that pluripotent human EC cells differentiate in response to OF-i and that this factor can m odulate the differentiation induced by retinoic acid. Like other membe rs of the transforming growth factor-beta super family, OF-i might pla y an inductive role in the early embryo. The results also suggest a po ssible therapeutic value for OF-i in the treatment of some germ cell t umors.