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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 22 MAY 2013
Copyright © 2013 AlphaMed Press
Volume 31, Issue 6, pages 1097–1106, June 2013
How to Cite
Przybyla, L. M., Theunissen, T. W., Jaenisch, R. and Voldman, J. (2013), Matrix Remodeling Maintains Embryonic Stem Cell Self-Renewal by Activating Stat3. STEM CELLS, 31: 1097–1106. doi: 10.1002/stem.1360
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.
- Issue published online: 22 MAY 2013
- Article first published online: 22 MAY 2013
- Accepted manuscript online: 13 FEB 2013 06:20AM EST
- Manuscript Accepted: 19 JAN 2013
- Manuscript Received: 11 SEP 2012
- National Institutes of Health. Grant Number: EB007278
- Singapore-MIT Alliance
- Sir Henry Wellcome Postdoctoral Fellowship. Grant Number: 098889
- NIH. Grant Number: HD 045022
- Embryonic stem cell;
- Extracellular matrix;
- Matrix metalloproteinase;
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