Nanoscale RGD Peptide Organization Regulates Cell Proliferation and Differentiation
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Nanoscale RGD Peptide Organization Regulates Cell Proliferation and Differentiation Susan Hsiong1,4, Kuen Yong Lee2, Eben Alsberg3, David Mooney1-4, Department of Chemical Engineering1, Biologic & Materials Science2, and Biomedical Engineering3. University of Michigan, Ann Arbor, MI. Division of Engineering and Applied Sciences4. Harvard University Laboratory for Cell and Tissue Engineering 40 Oxford St., Rm. 415 ESL Cambridge, MA 02138
ABSTRACT RGD (arginine-glycine-aspartic acid) containing peptide sequences, common cell attachment sites present in many extracellular matrix (ECM) proteins, mediate many important cellular processes. The role of nanoscale organization of RGD peptides in the regulation of the adhesion, proliferation and differentiation of both preosteoblasts (MC3T3-E1) and multipotential (D1) cell lines in vitro was investigated in this study. Alginate polymer chains with varying RGD peptide degree of substitution were mixed with unmodified polymer chains at different ratios to allow variation of RGD peptide spacing in the nanometer scale, independently of the overall bulk density of peptides presented from the material. Proliferation of both cell types was observed to be closely correlated to RGD island (defined as a cluster of RGD peptides) spacing, independently of overall bulk ligand density, following cell adhesion to alginate hydrogels. Increased RGD island spacing was observed to promote spreading of MC3T3-E1 cells while simultaneously suppressing their proliferation. However, increased RGD island spacing decreased spreading of D1 cells while also decreasing proliferation. Moreover, differentiation of preosteoblasts was significantly upregulated in response to decreased RGD island spacing, whereas differentiation of multipotential cells was modestly regulated by this variable. These results demonstrate that the nanoscale organization of adhesion ligands may be an important variable in controlling cell phenotype and function. In addition, cellular responses to nanoscale ligand organization differ depending on the cell type, and this may be related to the differentiation stage of the cells.
INTRODUCTION Cell adhesion to extracellular matrix (ECM) proteins via cell surface receptors mediates cellular processes such as proliferation, differentiation, and migration 1. The modification of biomaterials with adhesion ligands such as arginine-glycine-aspartic acid (RGD), a peptide sequence common in many ECM proteins, potentially allows control over cell fate. The distribution and density of adhesion ligands have been found to be important parameters regulating the proliferation and differentiation of various cell types
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. Furthermore, the spatial organization of adhesion ligand presentation is also important as adhesion ligands presented in a clustered manner (several ligands forming an adhesion island) as opposed to a random distribution were observed to promote cell adhesion and migration 4. However, the effects of nanoscale adhesion ligand organization on cell prolifera
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