Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks

  • An Erratum to this article was published on 26 June 2017

Abstract

Notwithstanding the remarkable progress in vascular network engineering, implanted bioengineered microvessels mostly fail to form anastomoses with the host vasculature. Here we demonstrate that implants containing assembled human vascular networks (A-grafts) fail to engraft owing to their inability to engage non-inflammatory host neutrophils upon implantation into mice. By contrast, unassembled vascular cells (U-grafts) readily engage alternatively polarized neutrophils, which in turn serve as indispensable mediators of vascular assembly and anastomosis. The depletion of host neutrophils abrogated vascularization in U-grafts, whereas an adoptive transfer of neutrophils fully restored vascularization in myeloid-depleted mice. Neutrophil engagement was regulated by secreted factors and was progressively silenced as the vasculature matured. Exogenous addition of factors from U-grafts re-engaged neutrophils and enhanced revascularization in A-grafts, a process that was recapitulated by blocking Notch signalling. Our data suggest that the pro-vascularization potential of neutrophils can be harnessed to improve the engraftment of bioengineered tissues.

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Figure 1: Engraftment of bioengineered microvascular networks.
Figure 2: Host neutrophils are indispensable for graft vascularization.
Figure 3: Host neutrophils are indispensable for graft vascularization in a syngeneic mouse C57BL/6 model.
Figure 4: Alternatively polarized neutrophils mediate U-graft vascularization.
Figure 5: Neutrophil activity regulated by secreted factors from the graft vasculature.
Figure 6: Notch inhibition promotes A-graft revascularization.

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Acknowledgements

We thank S.-C. S. Jaminet and D. Li (Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, USA) for quantitative reverse-transcription polymerase chain reaction analyses. Histology was supported by Core Facility of the Dana-Farber/Harvard Cancer Center (P30 CA06516). This work was supported by National Institutes of Health grants R00EB009096, R01AR069038, R01HL128452 and R21AI123883 to J.M.M.-M.

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R.-Z.L. and J.M.M.-M. conceived and designed the project. R.-Z.L., C.N.L., R.M.-L., J.N., P.Z., M.S., M.A.M. and J.M.M.-M. performed the experimental work. All authors discussed and analysed the data and edited the results. W.T.P., B.P. and S.E. provided crucial materials. R.-Z.L. and J.M.M.-M. wrote the manuscript.

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Correspondence to Juan M. Melero-Martin.

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The authors declare no competing financial interests.

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Lin, R., Lee, C., Moreno-Luna, R. et al. Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks. Nat Biomed Eng 1, 0081 (2017). https://doi.org/10.1038/s41551-017-0081

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