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Immobilized RGD concentration and proteolytic degradation synergistically enhance vascular sprouting within hydrogel scaffolds of varying modulus.

ABSTRACT: Insufficient vascularization limits the volume and complexity of engineered tissue. The formation of new blood vessels (neovascularization) is regulated by a complex interplay of cellular interactions with biochemical and biophysical signals provided by the extracellular matrix (ECM) necessitating the development of biomaterial approaches that enable systematic modulation in matrix properties. To address this need poly(ethylene) glycol-based hydrogel scaffolds were engineered with a range of decoupled and combined variations in integrin-binding peptide (RGD) ligand concentration, elastic modulus and proteolytic degradation rate using free-radical polymerization chemistry. The modularity of this system enabled a full factorial experimental design to simultaneously investigate the individual and interaction effects of these matrix cues on vascular sprout formation in 3?D culture. Enhancements in scaffold proteolytic degradation rate promoted significant increases in vascular sprout length and junction number while increases in modulus significantly and negatively impacted vascular sprouting. We also observed that individual variations in immobilized RGD concentration did not significantly impact 3?D vascular sprouting. Our findings revealed a previously unidentified and optimized combination whereby increases in both immobilized RGD concentration and proteolytic degradation rate resulted in significant and synergistic enhancements in 3?D vascular spouting. The above-mentioned findings would have been challenging to uncover using one-factor-at-time experimental analyses.

SUBMITTER: He YJ

PROVIDER: S-EPMC7185153 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Immobilized RGD concentration and proteolytic degradation synergistically enhance vascular sprouting within hydrogel scaffolds of varying modulus.

He Yusheng J YJ Santana Martin F MF Moucka Madison M Quirk Jack J Shuaibi Asma A Pimentel Marja B MB Grossman Sophie S Rashid Mudassir M MM Cinar Ali A Georgiadis John G JG Vaicik Marcella K MK Kawaji Keigo K Venerus David C DC Papavasiliou Georgia G

Journal of biomaterials science. Polymer edition 20191213 3

Insufficient vascularization limits the volume and complexity of engineered tissue. The formation of new blood vessels (neovascularization) is regulated by a complex interplay of cellular interactions with biochemical and biophysical signals provided by the extracellular matrix (ECM) necessitating the development of biomaterial approaches that enable systematic modulation in matrix properties. To address this need poly(ethylene) glycol-based hydrogel scaffolds were engineered with a range of dec ...[more]

PMID: 31774730

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Project description:Activation of vascular endothelial cells (ECs) by growth factors initiates a cascade of events during angiogenesis in vivo consisting of EC tip cell selection, sprout formation, EC stalk cell proliferation, and ultimately vascular stabilization by support cells. Although EC functional assays can recapitulate one or more aspects of angiogenesis in vitro, they are often limited by undefined substrates and lack of dependence on key angiogenic signaling axes. Here, we designed and characterized a chemically-defined model of endothelial sprouting behavior in vitro using human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs). We rapidly encapsulated iPSC-ECs at high density in poly(ethylene glycol) (PEG) hydrogel spheres using thiol-ene chemistry and subsequently encapsulated cell-dense hydrogel spheres in a cell-free hydrogel layer. The hydrogel sprouting array supported pro-angiogenic phenotype of iPSC-ECs and supported growth factor-dependent proliferation and sprouting behavior. iPSC-ECs in the sprouting model responded appropriately to several reference pharmacological angiogenesis inhibitors of vascular endothelial growth factor, NF-?B, matrix metalloproteinase-2/9, protein kinase activity, and ?-tubulin, which confirms their functional role in endothelial sprouting. A blinded screen of 38 putative vascular disrupting compounds from the US Environmental Protection Agency's ToxCast library identified six compounds that inhibited iPSC-EC sprouting and five compounds that were overtly cytotoxic to iPSC-ECs at a single concentration. The chemically-defined iPSC-EC sprouting model (iSM) is thus amenable to enhanced-throughput screening of small molecular libraries for effects on angiogenic sprouting and iPSC-EC toxicity assessment.Angiogenesis assays that are commonly used for drug screening and toxicity assessment applications typically utilize natural substrates like Matrigel(TM) that are difficult to spatially pattern, costly, ill-defined, and may exhibit lot-to-lot variability. Herein, we describe a novel angiogenic sprouting assay using chemically-defined, bioinert poly(ethylene glycol) hydrogels functionalized with biomimetic peptides to promote cell attachment and degradation in a reproducible format that may mitigate the need for natural substrates. The quantitative assay of angiogenic sprouting here enables precise control over the initial conditions and can be formulated into arrays for screening. The sprouting assay here was dependent on key angiogenic signaling axes in a screen of angiogenesis inhibitors and a blinded screen of putative vascular disrupting compounds from the US-EPA.

Dataset Information

Immobilized RGD concentration and proteolytic degradation synergistically enhance vascular sprouting within hydrogel scaffolds of varying modulus.

Publications

Immobilized RGD concentration and proteolytic degradation synergistically enhance vascular sprouting within hydrogel scaffolds of varying modulus.

Similar Datasets

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