We showed previously that proliferating human islet‐derived de‐differentiated cells (DIDs) exhibit many characteristics of mesenchymal stem cells. Dispersed DIDs can be induced by serum deprivation to undergo mesenchymal‐to‐epithelial transition and aggregate into epithelial cell clusters (ECCs). Conversely, ECCs can be induced to disperse and undergo epithelial‐to‐mesenchymal transition (EMT) by re‐addition of mammalian sera. In this study, we show that platelet‐derived growth factor BB (PDGF‐BB) mimics and mediates serum‐induced ECCs' dispersal accompanied by accumulation of cytoplasmic β‐catenin and a decrease in the levels of insulin and glucagon mRNAs. Moreover, we show that PDGF‐BB‐induced dispersal of ECCs is a more general phenomenon that occurs also with bone marrow mesenchymal stem cells (BM‐MSCs) and dermal fibroblasts (DFs). In DIDs, BM‐MSCs and DFs, PDGF decreased the levels of DKK1 mRNA, suggesting involvement of the Wnt signaling pathway. PDGF‐BB stimulated a significant increase in S473 phosphorylation of Akt and the PI3K specific inhibitor (PIP828) partially inhibited PDGF‐BB‐induced ECC dispersal. Lastly, the PDGF‐receptor (PDGF‐R) antagonist JNJ‐10198409 inhibited both PDGF‐BB – and serum‐induced ECC dispersal. Epidermal growth factor (EGF), which shares most of the PDGF signaling pathway, did not induce dispersal and only weakly stimulated Akt phosphorylation. Our data suggest that PDGF‐BB mediates serum‐induced DIDs dispersal, correlated with the activation of the PI3K‐Akt pathway. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.