Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs

Primitive hematopoietic stem cells are closely associated with discrete in vivo microenvironments. These 'niches' are thought to provide the molecular signals that mediate stem cell differentiation and self-renewal. We have dissected the fetal liver microenvironment into distinct cellular components by establishing an extensive panel of stromal cell 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 restricted 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 potential role of this molecule in hematopoietic stem/progenitor cell regulation. We show that the delta-like protein displays activity on purified stem cells by promoting the formation of 'cobblestone areas' of proliferation. These cobblestone areas contain both primitive high- proliferative potential progenitors and in vivo repopulating stem cells.