| Title | Molecularly designed alginate hydrogels susceptible to local proteolysis as three-dimensional cellular microenvironments |
| Publication Type | Journal Article |
| 2011 |
| Authors | Fonseca, KB, Bidarra, SJ, Oliveira, MJ, Granja, PL, Barrias, CC |
| Journal | Acta BiomaterialiaActa Biomater. |
| Volume | 7 |
| Issue | 4 |
| Pagination | 1674 - 1682 |
| Date Published | 2011/// |
| 17427061 (ISSN) |
| 3-D Cell culture, Alginate, Alginates, alginic acid, Amino Acid Sequence, article, cell adhesion, cell composition, Cell Count, Cell culture, Cell Culture Techniques, Cell Shape, cell structure, cell survival, cell viability, Cells, Cultured, controlled study, Enzyme Activation, enzyme activity, extracellular matrix, Extracellular matrix (ECM), gelatin, gelatinase A, Glucuronic Acid, Hexuronic Acids, human, human cell, Humans, hydrogel, Hydrogels, hydrolysis, matrix metalloproteinase, Matrix Metalloproteinases, Matrix metalloproteinases (MMPs), Mesenchymal stem cell, Mesenchymal Stem Cells, Molecular Sequence Data, morphology, peptide derivative, Peptides, phenotype, priority journal, prolylvalylglycylleucylisoleucylglycine, Protease-sensitive, protein cleavage, protein degradation, Protein Processing, Post-Translational, Subcellular Fractions, tumor microenvironment, unclassified drug, zymography |
| The development of sophisticated three-dimensional (3-D) cell culture microenvironments that recreate some of the complexity of the natural extracellular matrix (ECM) remains a challenging task. Here, the modification of alginate through partial crosslinking with a matrix metalloproteinase (MMP) cleavable peptide (proline-valine-glycine-leucine-isoleucine-glycine, PVGLIG) is described, and its use in the preparation of injectable, in situ crosslinkable hydrogel-like matrices is proposed. PVGLIG-grafted alginates were synthesized by carbodiimide chemistry and characterized. Their biological performance was evaluated by comparing the response of 3-D cultured mesenchymal stem cells (MSCs) to alginate hydrogels containing only cell-adhesion peptides (RGD-alginate) or both peptides (PVGLIG/RGD-alginate). After 1 week, cells remained essentially round within RGD-alginate, while they exhibited an elongated morphology within PVGLIG/RGD-alginate hydrogels, forming cellular networks. This suggests that cells were able to structurally reorganize the matrix, through enzymatic hydrolysis of PVGLIG residues, overcoming biophysical hydrogel resistance. As shown by gelatine-zymography, MSC presented higher activity of MMP-2 when cultured within alginate functionalized with MMP-sensitive peptide, suggesting that the cell's proteolytic phenotype was modulated by the matrix composition. Additionally, PVGLIG/RGD-alginate hydrogels were clearly degraded in cell culture. Taken together, the results demonstrate that the co-incorporation of MMP-labile peptides in cell-adhesive RGD-alginate hydrogels improved their performance as ECM analogues, providing a more dynamic and physiological 3-D cellular microenvironment. © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. |
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