Cell contact regulates fate choice by cortical stem cells

Cell fate is determined by intrinsic programs and external cues, such as so luble signals and cell-cell contact. Previous studies have demonstrated the roles of soluble factors in the proliferation and differentiation of corti cal stem cells and cell-cell contact in maintaining stem cells in a prolife rative state. In the present study, we focused on the effect of cell-cell i nteraction on cell-fate determination. We found that density could exert a strong influence on the cell-type composition when cortical stem cells diff erentiate. Multipotent stem cells, which normally gave rise to neurons, ast rocytes, and oligodendrocytes under high-density culture condition, differe ntiated almost exclusively into smooth muscle at low density. Clonal analys is indicated that smooth muscle and astrocytes were derived from a common p recursor and that the density effect on cell types used an instructive mech anism on the choice of fate rather than an effect of selective survival and /or proliferation. This instructive mechanism depended on the local and not the average density of the cells. This local signal could be mimicked by m embrane extract. These findings demonstrate the importance of membrane-boun d signals in specifying lineage and provide the first evidence for a short- range regulatory mechanism in cortical stem cell differentiation.