HEMATOPOIETIC ACTIVITY OF A STROMAL CELL TRANSMEMBRANE PROTEIN CONTAINING EPIDERMAL GROWTH FACTOR-LIKE REPEAT MOTIFS

Primitive hematopoietic stem cells are closely associated with discret e in vivo microenvironments. These ''niches'' are thought to provide t he molecular signals that mediate stem cell differentiation and self-r enewal. We have dissected the fetal liver microenvironment into distin ct cellular components by establishing an extensive panel of stromal c ell lines. One particular cell line maintains repopulating stem cells for prolonged in vitro culture periods. A subtraction cloning strategy has yielded a cDNA that encodes a cell surface glycoprotein with a re stricted pattern of expression among stromal cell lines. This molecule , previously identified as delta-like/preadipocyte factor-1, contains epidermal growth factor-like repeats that are related to those in the notch/delta/serrate family of proteins. We have investigated the poten tial role of this molecule in hematopoietic stem/progenitor cell regul ation. We show that the delta-like protein displays activity on purifi ed stem cells by promoting the formation of ''cobblestone areas'' of p roliferation. These cobblestone areas contain both primitive high-prol iferative potential progenitors and in vivo repopulating stem cells.