Adipose stromal cells differentiate along a smooth muscle lineage pathway upon endothelial cell contact via induction of activin A.

RATIONALE Adipose stromal cells (ASC) are therapeutically potent progenitor cells that possess properties of pericytes. In vivo, ASC in combination with endothelial cells (EC) establish functional multilayer vessels, in which ASC form the outer vessel layer and differentiate into mural cells. OBJECTIVE To identify factors responsible for ASC differentiation toward the smooth muscle cell phenotype via interaction with EC. METHODS AND RESULTS An in vitro model of EC cocultivation with ASC was used, in which EC organized into vascular cords, accompanied by ASC migration toward EC and upregulation of α-smooth muscle actin, SM22α, and calponin expression. Conditioned media from EC-ASC, but not from EC cultures, induced smooth muscle cell protein expression in ASC monocultures. EC-ASC cocultivation induced marked accumulation of activin A but not transforming growth factor-β1 in conditioned media. This was attributed to induction of activin A expression in ASC on contact with EC. Although transforming growth factor-β and activin A were individually sufficient to initiate expression of smooth muscle cell antigens in ASC, only activin A IgG blocked the effect of EC-ASC conditioned media. Although transforming growth factor-β was able to induce activin A expression in ASC, in cocultures this induction was transforming growth factor-β independent. In EC-ASC cocultures, activin A IgG or ALK4/5/7 receptor inhibitors blocked expression of α-smooth muscle actin in ASC in the absence of direct EC-cord contact, but this inhibition was circumvented in ASC by direct EC contact. CONCLUSIONS EC initiate a smooth muscle cell differentiation program in adjacent ASC and propagate this differentiation in distant ASC by induction of activin A expression.