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Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Nature Materials volume 16, pages 953–961 (2017)Cite this article

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Abstract

Integrin binding to bioengineered hydrogel scaffolds is essential for tissue regrowth and regeneration, yet not all integrin binding can lead to tissue repair. Here, we show that through engineering hydrogel materials to promote α3/α5β1 integrin binding, we can promote the formation of a space-filling and mature vasculature compared with hydrogel materials that promote αvβ3 integrin binding. In vitro, α3/α5β1 scaffolds promoted endothelial cells to sprout and branch, forming organized extensive networks that eventually reached and anastomosed with neighbouring branches. In vivo, α3/α5β1 scaffolds delivering vascular endothelial growth factor (VEGF) promoted non-tortuous blood vessel formation and non-leaky blood vessels by 10 days post-stroke. In contrast, materials that promote αvβ3 integrin binding promoted endothelial sprout clumping in vitro and leaky vessels in vivo. This work shows that precisely controlled integrin activation from a biomaterial can be harnessed to direct therapeutic vessel regeneration and reduce VEGF-induced vascular permeability in vivo.

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Figure 1: Endothelial cell sprouting in αvβ3-specific matrices displays clustered branches.
Figure 2: Endothelial cell sprout clustering is partially rescued with αv-blocking.
Figure 3: αvβ3 integrin engagement disrupts VE-cadherin in HUVECs.
Figure 4: Modulation of vascular patterning in skin using integrin-specific hydrogels.
Figure 5: Integrin-specific hydrogels modulate vascular patterning and permeability after stroke.
Figure 6: α3/α5β1 and αvβ3 integrin-specific materials regulate vascular patterning in vitro and in vivo.

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Acknowledgements

The authors would like to thank Y. Chen and X. Chen for their help with flow cytometry. The authors would like to acknowledge Developmental Studies Hybridoma Bank (DSHB) for providing antibodies P3G8, AIIB2, BIIG2 and 9H5. This work was supported by National Institutes of Health R01NS079691 (T.S.).

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, 90095, USA

    Shuoran Li, Lina R. Nih, Eunwoo Nam, Robert Dimatteo & Tatiana Segura

  2. Department of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, 30332, USA

    Haylee Bachman

  3. School of Optical and Electronic Information, Huazhong University of Science and Technology, Wuhan 430074, China

    Peng Fei

  4. Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, USA

    Peng Fei

  5. Department of Electrical Engineering, University of California, Los Angeles, California, 90095, USA

    Yilei Li

  6. NovuMind Inc., Santa Clara, California, 95054, USA

    Yilei Li

  7. Department of Medicine, Neurology, University of California, Los Angeles, California, 90095, USA

    S. Thomas Carmichael

  8. Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, 22908, USA

    Thomas H. Barker

  9. Department of Medicine, Dermatology, University of California, Los Angeles, California, 90095, USA

    Tatiana Segura

  10. Department of Bioengineering, University of California, Los Angeles, California, 90095, USA

    Tatiana Segura

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  1. Shuoran Li
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Contributions

S.L. contributed to conceptual design, experimental execution, and troubleshooting. L.R.N. contributed to conceptual design, experimental execution, and troubleshooting for experiments involving the middle cerebral artery occlusion stroke model (Fig. 5). H.B. contributed to conceptual design, troubleshooting and production of the Fn9∗10 and Fn9(4G)10 fibronectin fragments. P.F. contributed to conceptual design and troubleshooting of sheet confocal imaging for the modified Matrigel plug assay. Y.L. contributed to the conceptual design and experimental execution of the Matlab code used for cell migration analysis in Supplementary Fig. 1e, f. E.N. contributed to experimental execution and troubleshooting for experiments involving VE-cadherin quantification. R.D. contributed to the conceptual design and experimental execution of the Matlab code used for space-filling analysis in Fig. 4d. S.T.C. contributed to the conceptual design, and data interpretation for Fig. 5. T.H.B. contributed to conceptual design and troubleshooting of the Fn9∗10 and Fn9(4G)10 fibronectin fragments. T.S. contributed to conceptual design, and oversaw all experimental design and interpretation. While S.L. and T.S. wrote the first draft of the manuscript all authors read and gave comments, especially with regards to their experimental section and analysis.

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Correspondence to Tatiana Segura.

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The authors declare no competing financial interests.

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Li, S., Nih, L., Bachman, H. et al. Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability. Nature Mater 16, 953–961 (2017). https://doi.org/10.1038/nmat4954

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