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 towards the smooth muscle cell (SMC) phenotype via interaction with EC.
Methods and Results: An in vitro model of EC co-cultivation with ASC was employed, in which EC organized into vascular cords, accompanied by ASC migration towards EC and up-regulation of αSMA, SM22α, and calponin expression. Conditioned media (CM) from EC-ASC, but not from EC cultures, induced SMC protein expression in ASC monocultures. EC-ASC co-cultivation induced marked accumulation of activin A, but not TGFβ1 in CM. This was attributed to induction of activin A expression in ASC upon contact with EC. While TGFβ and activin A were individually sufficient to initiate expression of SMC antigens in ASC, only activin A IgG blocked the effect of EC-ASC CM. While TGFβ was able to induce activin A expression in ASC, in co-cultures this induction was TGFβ-independent. In EC-ASC co-cultures activin A IgG or ALK4/5/7 receptor inhibitors blocked expression of αSMA 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 SMC differentiation program in adjacent ASC, and propagate this differentiation in distant ASC, by induction of activin A expression.
- activin A
- adipose stromal cells
- mural cells
- endothelial cell
- mesenchymal stem cell
- adipose tissue
- smooth muscle differentiation
- Received March 24, 2014.
- Revision received August 6, 2014.
- Accepted August 11, 2014.