Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells
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Griffith_Sustained epidermal.pdf
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Author(s)
Platt, Manu O.
Roman, Arian J.
Wells, Alan
Lauffenburger, Douglas A.
Griffith, Linda G.
Date Issued
June 2009
Journal
Journal of Cellular Physiology
Publisher
Wiley Blackwell
Citation
Platt, Manu O. et al. “Sustained Epidermal Growth Factor Receptor Levels and Activation by Tethered Ligand Binding Enhances Osteogenic Differentiation of Multi-potent Marrow Stromal Cells.” Journal of Cellular Physiology 221.2 (2009): 306–317.
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Author's final manuscript
Abstract
Epidermal growth factor receptor (EGFR)-mediated signaling helps regulate bone development and healing through its effects on osteogenic cells. Here, we show how EGFR activity and osteogenic differentiation responses in primary human bone marrow-derived multipotent stromal cells (MSCs) are influenced by presenting covalently tethered epidermal growth factor (tEGF) on the culture substratum, a presentation mode that reduces EGFR internalization and restricts signaling to the cell surface. In both absence and presence of tEGF, MSCs increase expression levels of EGFR and its heterodimerization partner HER2 during the course of osteogenic differentiation. tEGF substrata increased levels of phosphorylated EGFR and phosphorylated extracellular regulated kinase (ERK) compared to control substrata, and these elevations were associated with a twofold enhancement of MSC alkaline phosphatase activity at day 7 and matrix mineralization at day 21. Surprisingly, addition of soluble EGF (sEGF) to cells cultured on tEGF substrata reduces osteogenic differentiation, even though EGFR signaling is more strongly activated in acute, short-term manner by sEGF treatment than by tEGF treatment. A striking concomitant result of the sEGF effects is near-complete downregulation of EGFR and HER2, demonstrating that the tEGF/EGFR interaction is dynamically reversible even though temporally sustained. Taken together, our results show that enhanced MSC osteogenic differentiation corresponds to a sustained combination of receptor expression and ligand presentation, both of which are maintained by tEGF.
Description
Author Manuscript 2011 April 29.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1002/jcp.21854
