Matrix Remodeling Maintains ESC Self-Renewal by Activating Stat3
Author(s)Przybyla, Laralynne M.; Theunissen, Thorold W.; Jaenisch, Rudolf; Voldman, Joel
Matrix Remodeling Maintains Embryonic Stem Cell Self-Renewal by Activating Stat3
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Whitehead Institute for Biomedical Research
Przybyla, Laralynne M., Thorold W. Theunissen, Rudolf Jaenisch, and Joel Voldman. “Matrix Remodeling Maintains Embryonic Stem Cell Self-Renewal by Activating Stat3.” STEM CELLS 31, no. 6 (May 22, 2013): 1097–1106.
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