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

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Abstract

The development of stable, functional microvessels remains an important obstacle to overcome for tissue engineered organs and treatment of ischemia. Endothelial progenitor cells (EPCs) are a promising cell source for vascular tissue engineering as they are readily obtainable and carry the potential to differentiate towards all endothelial phenotypes. The aim of this study was to investigate the ability of human umbilical cord blood-derived EPCs to form vessel-like structures within a tissue engineering scaffold material, a cell-adhesive and proteolytically degradable polyethylene glycol hydrogel. EPCs in co-culture with angiogenic mural cells were encapsulated in hydrogel scaffolds by mixing with polymeric precursors and using a mild photocrosslinking process to form hydrogels with homogeneously dispersed cells. EPCs formed 3D microvessels networks that were stable for at least 30 days in culture, without the need for supplemental angiogenic growth factors. These 3D EPC microvessels displayed aspects of physiological microvasculature with lumen formation, expression of endothelial cell proteins (connexin 32, VE-cadherin, eNOS), basement membrane formation with collagen IV and laminin, perivascular investment of PDGFR-β and α-SMA positive cells, and EPC quiescence (<1% proliferating cells) by 2 weeks of co-culture. Our findings demonstrate the development of a novel, reductionist system that is well-defined and reproducible for studying progenitor cell-driven microvessel formation.

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Acknowledgments

This study was supported by NIH Grant 5R01HL097520 and NSF Graduate Research Fellowship 1106401 to E.B.P. The authors would like to acknowledge Ms. Yan Wu for her assistance in mechanical testing.

Conflicts of interest

Erica B. Peters, Nicolas Christoforou, Kam W. Leong, George A. Truskey, and Jennifer L. West declare that they have no conflicts of interest.

Ethical Standards

No human or animal studies were carried out by the authors of this article.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Duke University, Fitzpatrick CIEMAS Building, Room 1427, Box 90281, Durham, NC, 27708, USA

    Erica B. Peters, George A. Truskey & Jennifer L. West

  2. Department of Biomedical Engineering, Khalifa University, P.O. Box 127788, Abu Dhabi, United Arab Emirates

    Nicolas Christoforou

  3. Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, Mail Code 8904, New York, NY, 10027, USA

    Kam W. Leong

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  1. Erica B. Peters
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Correspondence to Erica B. Peters.

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Supplemental Fig. 1

Representative histograms from flow cytometry characterization of EPCs at passage 3 showing expression for EC-associated marker expression for CD31, CD105, CD309/VEGFR2, CD146, and CD34 (A) and lack of expression for leukocyte-associated markers CD115 and CD45 and mesenchymal stem cell/fibroblast-associated marker CD90 (B). The y-axis is the percentage of the maximum number of events within the FITC or PE channel, the x-axis indicates the relative fluorescence intensity of PE or FITC expression, calculated by integration of fluorescence over the cell area. The percentage of positive cells for each condition is in reference to the negative control, which consisted of mouse IgG1 isotype, indicated by a red outline. A minimum of 9000 events were analyzed per condition (TIFF 3249 kb)

Supplemental Fig. 2

Characterization of SMCs for mural cell-associated protein markers α-SMA, calponin, PDGFR-β, and Ephrin-B2. Scale bar equals 100 µm (TIFF 10067 kb)

Supplemental Fig. 3

(A) Representative images of microvessel formation throughout the hydrogel by GFP-transduced HUVECs and hCB-EPCs (EPCs) in 1:1 co-culture with SMCs (not visible) after 14 days of culture. Scale bar equals 50 µm. (B) Representative images of hCB-EPC (EPC) monoculture controls at days 7 and 14 after encapsulation. Images were taken within a 50-µm depth from the gel surface. Scale bar equals 250 µm. (C) Representative images depicting the localization of SMCs, transduced with GFP, near microvessels formed by hCB-EPCs (EPCs) or HUVECs, transduced with tomato-fluorescent protein, after 14 days of culture. Images were taken within a 50-µm depth from the gel surface. Scale bar equals 250 µm. (D) Representative image of EPC microvessels, transduced with GFP, after 30 days of in vitro co-culture with SMCs (not visible) at a 1:1 ratio. Images were taken within a 50-µm depth from the gel surface. Scale bar equals 250 µm (TIFF 16793 kb)

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Peters, E.B., Christoforou, N., Leong, K.W. et al. Poly(Ethylene Glycol) Hydrogel Scaffolds Containing Cell-Adhesive and Protease-Sensitive Peptides Support Microvessel Formation by Endothelial Progenitor Cells. Cel. Mol. Bioeng. 9, 38–54 (2016). https://doi.org/10.1007/s12195-015-0423-6

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