Matrix Remodeling Maintains ESC Self-Renewal by Activating Stat3

• Main Authors: Przybyla, Laralynne M. (Contributor), Theunissen, Thorold W. (Author), Jaenisch, Rudolf (Contributor), Voldman, Joel (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science (Contributor), Whitehead Institute for Biomedical Research (Contributor)
• Format: Article
• Language: English
• Published: Wiley Blackwell, 2014-10-21T15:00:38Z.
• Subjects: Article
• Online Access: Get fulltext

 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.