Poly(Ethylene Glycol) Hydrogel Scaffolds Containing Cell-Adhesive and Protease-Sensitive Peptides Support Microvessel Formation by Endothelial Progenitor Cells

Peters, Erica B.; Christoforou, Nicolas; Leong, Kam W.; Truskey, George A.; West, Jennifer L.

doi:10.1007/s12195-015-0423-6

Cited by 68 publications

(46 citation statements)

References 65 publications

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“…Although functionalized PEG hydrogels have been used for epithelial (31), endothelial (32), connective tissue (33), and stromal cells (34), co-cultures of epithelial and stromal cells require tuning matrix properties to meet the needs of both cell types (35). Hence, we first established an endometrial stromal and epithelial co-culture in functionalized PEG gels as a model of a complex, multicellular, 3D system that can be interrogated through SrtA-mediated gel dissolution.…”

Section: Resultsmentioning

confidence: 99%

On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial-stromal communication networks

et al. 2017

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Methods to parse paracrine epithelial-stromal communication networks are a vital need in drug development, as disruption of these networks underlies diseases ranging from cancer to endometriosis. Here, we describe a modular, synthetic, and dissolvable extracellular matrix (MSD-ECM) hydrogel that fosters functional 3D epithelial-stromal co-culture, and that can be dissolved on-demand to recover cells and paracrine signaling proteins intact for subsequent analysis. Specifically, synthetic polymer hydrogels, modified with cell-interacting adhesion motifs and crosslinked with peptides that include a substrate for cell-mediated proteolytic remodeling, can be rapidly dissolved by an engineered version of the microbial transpeptidase Sortase A (SrtA) if the crosslinking peptide includes a SrtA substrate motif and a soluble second substrate. SrtA-mediated dissolution affected only 1 of 31 cytokines and growth factors assayed, whereas standard protease degradation methods destroyed about half of these same molecules. Using co-encapsulated endometrial epithelial and stromal cells as one model system, we show that the dynamic cytokine and growth factor response of co-cultures to an inflammatory cue is richer and more nuanced when measured from SrtA-dissolved gel microenvironments than from the culture supernate. This system employs accessible, reproducible reagents and facile protocols; hence, has potential as a tool in identifying and validating therapeutic targets in complex diseases.

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Section: Resultsmentioning

confidence: 99%

On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial-stromal communication networks

et al. 2017

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“…Our model also provides a tool to investigate matrix remodeling in organotypic capillary morphogenesis with specific EC and stromal cell combinations. Finally, the unique matrix‐centric perspective of these studies provides strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the relative roles of matrix metalloproteinase‐ and plasmin‐mediated matrix degradation during capillary morphogenesis using engineered hydrogels

et al. 2019

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Extracellular matrix (ECM) remodeling is essential for the process of capillary morphogenesis. Here we employed synthetic poly(ethylene glycol) (PEG) hydrogels engineered with proteolytic specificity to either matrix metalloproteinases (MMPs), plasmin, or both to investigate the relative contributions of MMP‐ and plasmin‐mediated ECM remodeling to vessel formation in a 3D‐model of capillary self‐assembly analogous to vasculogenesis. We first demonstrated a role for both MMP‐ and plasmin‐mediated mechanisms of ECM remodeling in an endothelial‐fibroblast co‐culture model of vasculogenesis in fibrin hydrogels using inhibitors of MMPs and plasmin. When this co‐culture model was employed in engineered PEG hydrogels with selective protease sensitivity, we observed robust capillary morphogenesis only in MMP‐sensitive matrices. Fibroblast spreading in plasmin‐selective hydrogels confirmed this difference was due to protease preference by endothelial cells, not due to limitations of the matrix itself. In hydrogels engineered with crosslinks that were dually susceptible to MMPs and plasmin, capillary morphogenesis was unchanged. These findings highlight the critical importance of MMP‐mediated degradation during vasculogenesis and provide strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2507–2516, 2019.

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“…[26, 27] Similarly, PEO as a synthetic polyether (also known as poly(ethylene glycol) (PEG) at small molecular weights), is prevalently used as hydrogel scaffolds for biomedical applications owing to its biocompatibility, inertness, and readily available molecular modifications. [28] Studies have shown that the addition of PEG increases the strength of hydrogen bonding between gelatin chains and results in phase separation of the gelatin/PEG aqueous solutions at both above and below the gelation temperature of gelatin. [29, 30] …”

mentioning

confidence: 99%

Aqueous Two‐Phase Emulsion Bioink‐Enabled 3D Bioprinting of Porous Hydrogels

et al. 2018

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The three-dimensional (3D) bioprinting technology provides programmable and customizable platforms to engineer cell-laden constructs mimicing human tissues for a wide range of biomedical applications. However, the encapsulated cells are often restricted in spreading and proliferation by dense biomaterial networks from gelation of bioinks. Herein, we report a novel cell-benign approach to directly bioprint porous-structured hydrogel constructs by using an aqueous two-phase emulsion bioink. The bioink, which contains two immiscible aqueous phases of cell/gelatin methacryloyl (GelMA) mixture and poly(ethylene oxide) (PEO), is photocrosslinked to fabricate predesigned cell-laden hydrogel constructs by extrusion bioprinting or digital micromirror device-based stereolithographic bioprinting. Porous structure of the 3D-bioprinted hydrogel construct is formed by subsequently removing the PEO phase from the photocrosslinked GelMA hydrogel. Three different cells (human hepatocellular carcinoma cells, human umbilical endothelial cells, and NIH/3T3 mouse embryonic fibroblasts) within the 3D-bioprinted porous cell-laden hydrogel patterns showed enhanced cell viability, spreading, and proliferation compared to the standard (i.e. non-porous) hydrogel constructs. The new 3D bioprinting strategy is believed to provide a robust and versatile platform to engineer porous-structured tissue constructs and their models for a variety of applications in tissue engineering, regenerative medicine, and personalized therapeutics.

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Poly(Ethylene Glycol) Hydrogel Scaffolds Containing Cell-Adhesive and Protease-Sensitive Peptides Support Microvessel Formation by Endothelial Progenitor Cells

Cited by 68 publications

References 65 publications

On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial-stromal communication networks

On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial-stromal communication networks

Deciphering the relative roles of matrix metalloproteinase‐ and plasmin‐mediated matrix degradation during capillary morphogenesis using engineered hydrogels

Aqueous Two‐Phase Emulsion Bioink‐Enabled 3D Bioprinting of Porous Hydrogels

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