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Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates

An Author Correction to this article was published on 19 May 2021

This article has been updated

Abstract

Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

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Figure 1: Numerous immune populations respond to implanted alginate spheres.
Figure 2: The immune response to implanted biomaterial alginate is long-lived.
Figure 3: Innate immune macrophage function is required for fibrosis of alginate.
Figure 4: Macrophages, and not neutrophils, are required for fibrosis of alginate.
Figure 5: CSF1R-dependent macrophages recruit fibrosis-potentiating B cells via CXCL13.
Figure 6: Essential fibrotic cascade players are also increased in non-human primates.

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Acknowledgements

This work was supported by the Juvenile Diabetes Research Foundation (JDRF) (Grant 17-2007-1063), the Leona M. and Harry B. Helmsley Charitable Trust Foundation (Grants 09PG-T1D027 and 2015PG-T1D063), the National Institutes of Health (Grants EB000244, EB000351, DE013023 and CA151884), and through a generous gift from the Tayebati Family Foundation. J.C.D. was supported by JDRF postdoctoral fellowship (Grant 3-PDF-2015-91-A-N). O.V. was supported by JDRF and DOD/CDMRP postdoctoral fellowships (Grants 3-2013-178 and W81XWH-13-1-0215, respectively). J.O. is supported by the National Institutes of Health (NIH/NIDDK) R01DK091526 and the Chicago Diabetes Project. D.L.G. is supported by the National Institutes of Health (NIH/NIDDK) UC4 DK104218. The authors would like to acknowledge the use of resources at W. M. Keck Biological Imaging Facility (Whitehead Institute), and Microscopy, Histology, Whole Animal Imaging, and Flow Cytometry Core Facilities (Swanson Biotechnology Center, David H. Koch Institute for Integrative Cancer Research at MIT).

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J.C.D. and D.G.A. designed experiments, analysed data and wrote the manuscript. J.C.D., O.V., A.J.V., H.H.T., S.F., M.M., J.L., A.B., A.C., S.A.-D., M.G., A.S., S.J., M.W., S.S., K.T., M.C., E.L., N.D., R.T., M.Q. and J.O. performed experiments. J.C.D. and H.H.T. performed statistical analyses of data sets and aided in the preparation of displays communicating data sets. J.O. and D.L.G. provided conceptual advice and technical support. R.L. and D.G.A. supervised the study. All authors discussed the results and assisted in the preparation of the manuscript.

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Correspondence to Daniel G. Anderson.

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Doloff, J., Veiseh, O., Vegas, A. et al. Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nature Mater 16, 671–680 (2017). https://doi.org/10.1038/nmat4866

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