Synergistic effects of tethered growth factors and adhesion ligands on DNA synthesis and function of primary hepatocytes cultured on soft synthetic hydrogels

Geeta Mehta

Associate Professor

3044 NCRC, Building 28

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Geeta Mehta, Courtney M Williams, Luis Alvarez, Martha Lesniewski, Roger D Kamm, and Linda G Griffith (2010)

BIOMATERIALS, 31(17):4657-4671.

The composition, presentation, and spatial orientation of extracellularmatrix molecules and growth factors are key regulators of cell behaviorHere, we used self-assembling peptide nanofiber gels as a modularscaffold to investigate how fibronectin-derived adhesion ligands anddifferent modes of epidermal growth factor (EGF) presentationsynergistically regulate multiple facets of primary rat hepatocytebehavior in the context of a soft gel. In the presence of soluble EGF,inclusion of dimeric RGD and the heparin binding domain from fibronectin(HB) increased hepatocyte aggregation, spreading, and metabolic functioncompared to unmodified gels or gels modified with a single motif, butunlike rigid substrates, gels failed to induce DNA synthesis. TetheredEGF dramatically stimulated cell aggregation and spreading under alladhesive ligand conditions and also preserved metabolic function.Surprisingly, tethered EGF elicited DNA synthesis on gels with RGD andHB. Phenotypic differences between soluble and tethered EGF stimulationof cells on peptide gels are correlated with differences in expressionand phosphorylation the EGF receptor and its heterodimerization partnerErbB2, and activation of the downstream signaling node ERK1/2 Thesemodular matrices reveal new facets of hepatocellular biology in cultureand may be more broadly useful in culture of other soft tissues. (C)2010 Elsevier Ltd All rights reserved

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