Transforming Growth Factor-β and Notch Signaling Mediate Stem Cell Differentiation into Smooth Muscle Cells§

Authors

  • Kyle Kurpinski,

    1. Joint Graduate Program in Bioengineering, University of California Berkeley, Berkeley, California, and University of California San Francisco, San Francisco, California, USA
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  • Hayley Lam,

    1. Joint Graduate Program in Bioengineering, University of California Berkeley, Berkeley, California, and University of California San Francisco, San Francisco, California, USA
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  • Julia Chu,

    1. Joint Graduate Program in Bioengineering, University of California Berkeley, Berkeley, California, and University of California San Francisco, San Francisco, California, USA
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  • Aijun Wang,

    1. Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
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  • Ahra Kim,

    1. Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
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  • Eric Tsay,

    1. Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
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  • Smita Agrawal,

    1. Department of Chemical Engineering, University of California, Berkeley, Berkeley, California, USA
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  • David V. Schaffer,

    1. Joint Graduate Program in Bioengineering, University of California Berkeley, Berkeley, California, and University of California San Francisco, San Francisco, California, USA
    2. Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
    3. Department of Chemical Engineering, University of California, Berkeley, Berkeley, California, USA
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  • Song Li

    Corresponding author
    1. Joint Graduate Program in Bioengineering, University of California Berkeley, Berkeley, California, and University of California San Francisco, San Francisco, California, USA
    2. Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
    • Department of Bioengineering, University of California, Berkeley, B108A Stanley Hall, Berkeley, CA 94720-1762

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    • Telephone: (510) 666-2799; Fax: (510) 666-3381


  • Author contribution: K.K., H.L.: Conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; J.C.: Collection and assembly of data, data analysis; A.W., A.K., E.T.: Collection and assembly of data; S.A.: Collection and assembly of data, provision of study material; D.S.: Conception and design, provision of study material, manuscript writing, financial support; S.L.: Conception and design, data analysis and interpretation, manuscript writing, financial support.

  • First published online in STEM CELLS EXPRESS February 9, 2010.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

Abstract

The differentiation of stem cells into smooth muscle cells (SMCs) plays an important role in vascular development and remodeling. In addition, stem cells represent a potential source of SMCs for regenerative medicine applications such as constructing vascular grafts. Previous studies have suggested that various biochemical factors, including transforming growth factor-β (TGF-β) and the Notch pathway, may play important roles in vascular differentiation. However, the interactions of these two signaling pathways in the differentiation of bone marrow mesenchymal stem cells (MSCs) have not been clearly defined. In this study, we profiled the gene expression in MSCs in response to TGF-β, and showed that TGF-β induced Notch ligand Jagged 1 (JAG1) and SMC markers, including smooth muscle α-actin (ACTA2), calponin 1 (CNN1), and myocardin (MYOCD), which were dependent on the activation of SMAD3 and Rho kinase. In addition, knocking down JAG1 expression partially blocked ACTA2 and CNN1 expression and completely blocked MYOCD expression, suggesting that JAG1 plays an important role in TGF-β-induced expression of SMC markers. On the other hand, the activation of Notch signaling induced the expression of SMC markers in MSCs and human embryonic stem cells (hESCs). Notch activation in hESCs also resulted in an increase of neural markers and a decrease of endothelial markers. These results suggest that Notch signaling mediates TGF-β regulation of MSC differentiation and that Notch signaling induces the differentiation of MSCs and hESCs into SMCs, which represents a novel mechanism involved in stem cell differentiation. STEM CELLS 2010;28:734–742

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