• Open Access

Matrix Remodeling Maintains Embryonic Stem Cell Self-Renewal by Activating Stat3§

Authors

  • Laralynne M. Przybyla,

    1. Department of Biology and
    Search for more papers by this author
  • Thorold W. Theunissen,

    1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, USA
    Search for more papers by this author
  • Rudolf Jaenisch,

    1. Department of Biology and
    2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, USA
    Search for more papers by this author
  • Joel Voldman

    Corresponding author
    1. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    • Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
    Search for more papers by this author
    • Telephone: 617-253-2094; Fax: 617-258-5845


  • Author contributions: L.M.P.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; T.W.T.: collection of data, data analysis and interpretation, and manuscript editing; R.J.: experimental design and manuscript editing; J.V.: conception and design, assembly of data, data interpretation, and manuscript writing.

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

  • §

    first published online in STEM CELLS EXPRESS February 13, 2013.

Abstract

While a variety of natural and synthetic matrices have been used to influence embryonic stem cell (ESC) self-renewal or differentiation, and ESCs also deposit a rich matrix of their own, the mechanisms behind how extracellular matrix affects cell fate are largely unexplored. The ESC matrix is continuously remodeled by matrix metalloproteinases (MMPs), a process that we find is enhanced by the presence of mouse embryonic fibroblast feeders in a paracrine manner. Matrix remodeling by MMPs aids in the self-renewal of ESCs, as inhibition of MMPs inhibits the ability of ESCs to self-renew. We also find that addition of the interstitial collagenase MMP1 is sufficient to maintain long-term leukemia inhibitory factor (LIF)-independent mouse ESC (mESC) self-renewal in a dose-dependent manner. This remarkable ability is due to the presence of endogenously produced self-renewal-inducing signals, including the LIF-family ligand ciliary neurotrophic factor, that are normally trapped within the ECM and become exposed upon MMP-induced matrix remodeling to signal through JAK and Stat3. These results uncover a new role for feeder cells in maintaining self-renewal and show that mESCs normally produce sufficient levels of autocrine-acting pro-self-renewal ligands. STEM Cells 2013;31:1097–1106

Ancillary