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(Circulation Research. 2004;94:1571.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Msx2 and Necdin Combined Activities Are Required for Smooth Muscle Differentiation in Mesoangioblast Stem Cells

Silvia Brunelli, Enrico Tagliafico, Fernanda G. De Angelis, Rossana Tonlorenzi, Silvia Baesso, Sergio Ferrari, Michio Niinobe, Kazuaki Yoshikawa, Robert J. Schwartz, Irene Bozzoni, Stefano Ferrari, Giulio Cossu

From the Stem Cell Research Institute (S Brunelli, R.T., S Baesso, G.C.), DIBIT-HSR, Milan, Italy; Department of Biomedical Science (E.T., Se Ferrari, St Ferrari), University of Modena, Modena, Italy; Institute Pasteur Fondazione Cenci-Bolognetti (F.G.D.A., I.B.), Department of Genetics and Molecular Biology and IPBM, University "La Sapienza," Rome, Italy; Division of Regulation of Macromolecular Functions (M.N., K.Y.), Institute for Protein Research, Osaka University, Yamadaoka Suita, Osaka, Japan; The Center for Cardiovascular Development (R.J.S.), Baylor College of Medicine, Houston, Tex; and Department of Histology and Embryology (G.C.), University "La Sapienza," Rome, Italy.

Correspondence to Dr Giulio Cossu, Stem Cell Research Institute, DIBIT-H San Raffaele, via Olgettina 58, 20132 Milan, Italy. E-mail cossu.giulio{at}hsr.it

Little is known about the molecular mechanism underlying specification and differentiation of smooth muscle (SM), and this is, at least in part, because of the few cellular systems available to study the acquisition of a SM phenotype in vitro. Mesoangioblasts are vessel-derived stem cells that can be induced to differentiate into different cell types of the mesoderm, including SM. We performed a DNA microarray analysis of a mesoangioblast clone that spontaneously expresses an immature SM phenotype and compared it with a sister clone mainly composed of undifferentiated progenitor cells. This study allowed us to define a gene expression profile for "stem" cells versus smooth muscle cells (SMCs) in the absence of differentiation inducers such as transforming growth factor ß. Two transcription factors, msx2 and necdin, are expressed at least 100 times more in SMCs than in stem cells, are coexpressed in all SMCs and tissues, are induced by transforming growth factor ß, and, when coexpressed, induce a number of SM markers in mesoangioblast, fibroblast, and endothelial cell lines. Conversely, their downregulation through RNA interference results in a decreased expression of SM markers. These data support the hypothesis that Msx2 and necdin act as master genes regulating SM differentiation in at least a subset of SMCs.

Key Words: muscle, smooth • embryo • mesoangioblast

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