Science - USA (2020-04-10)

and hNCCs that were separate from any clus-
ter diminished over time (fig. S8, G to M).
We have developed an intravital imaging
window for manipulating and visualizing live
mouse embryos in vivo from E9.5 until birth.
The capability to image embryos in utero at
high resolution opens new avenues for inves-
tigation, including brain formation, peripheral
nerve development, placental development,
birth defects, gene editing, immune system
development, environmental effects, and in-
terspecies chimera.

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ACKNOWLEDGMENTS
We thank L. Cameron (Duke University) and M. Itano (University
of North Carolina) for assistance with two-photon microscopy,
and the Innovation Co-Lab at Duke University. This work was supported
by NSFC81670468, 2017KJXX-43, 2018SF-208, China Scholarship
Council (to Q.H.); by NIH R35GM122465 and DK119795 (to X.S.);
by the Emerald Foundation, the Leo Foundation, and Melanoma
Research Foundation (to R.J. and M.A.C.); by NIH R37HD045022,
1R01-NS088538, and 5R01-MH104610 (to R.J.); by NIH NS083897,
NS098176, NS110388 and MH119813 (to D.L.S.); and by NIH R35

CA197616 (to D.G.K.).Author contributions:Q.H. and X.S.

designed the experiments. Q.H. performed the experiments with

assistance from A.G., N.R., E.W., K.X., P.M., L.W., C.B., V.R., Y.W.,

M.N., C.W.W., P.K.L.M., A.R.D., D.G.K., and Y.K.; M.A.C., S.Z.,

and R.J. designed and performed the chimeras experiments. F.C.A.

and D.L.S. designed and performed the in utero electroporation

experiments. G.D., P.H., and A.A. designed and generated the AAV

vectors. J.M. and B.C. assisted with embryo imaging and handling.

Competing interests:The authors declare no competing interests.

Data and materials availability:All data are available in the main

text or the supplementary materials.

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/368/6487/181/suppl/DC1

Materials and Methods

Figs. S1 to S8

References ( 39 – 46 )

Movies S1 to S9

29 October 2019; accepted 16 March 2020

10.1126/science.aba0210

IMMUNOLOGY

Dendritic cell–derived hepcidin sequesters iron from

the microbiota to promote mucosal healing

Nicholas J. Bessman1,2,3, Jacques R. R. Mathieu4,5*, Cyril Renassia4,5*, Lei Zhou1,2,3,

Thomas C. Fung1,2,3, Keith C. Fernandez1,2,3, Christine Austin^6 , Jesper B. Moeller1,2,3,7,

Sara Zumerle4,5†, Sabine Louis4,5, Sophie Vaulont4,5, Nadim J. Ajami^8 , Harry Sokol^9 ,

Gregory G. Putzel^1 , Tara Arvedson^10 , Robbyn E. Sockolow^11 , Samira Lakhal-Littleton^12 ,

Suzanne M. Cloonan13,14, Manish Arora^6 , Carole Peyssonnaux4,5‡, Gregory F. Sonnenberg1,2,3‡

Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the

importance and regulation of these changes remain unclear. We found that hepcidin, the

master regulator of systemic iron homeostasis, is required for tissue repair in the mouse

intestine after experimental damage. This effect was independent of hepatocyte-derived

hepcidin or systemic iron levels. Rather, we identified conventional dendritic cells (cDCs) as

a source of hepcidin that is induced by microbial stimulation in mice, prominent in the

inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted

on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the

microbiota and consequently facilitated intestinal repair. Collectively, these results identify a

pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through

means of nutritional immunity.

I

nflammatory bowel disease (IBD), colorec-

tal cancer, and gastrointestinal infections

cause tissue inflammation that drives bleed-

ing, malabsorption, and diarrhea ( 1 – 3 ). As

a result, patients frequently exhibit ane-

mia that is difficult to treat, and bleeding in-

troduces a new source of iron to the intestine

( 4 , 5 ). Hepcidin, the master regulator of sys-

temic iron homeostasis, is produced as a pep-

tide hormone from the liver and promotes

degradationofthecellularironeffluxtrans-

porter ferroportin ( 4 , 6 – 10 ). Ferroportin is ex-

pressed on red pulp macrophages and the

basolateral surface of duodenal enterocytes,

where it facilitates iron recycling from senes-

cent red blood cells and import of dietary iron,

respectively ( 4 , 6 – 10 ). Despite these advances,

it remains unclear whether hepcidin has a role

in gastrointestinal health or disease.

To address this, we exposed wild-type

(Hamp+/+) and hepcidin-deficient (Hamp–/–)

mice to a model of intestinal tissue damage,

inflammation, and repair by administering

dextran sodium sulfate (DSS) in their drinking

water. During DSS administration,Hamp+/+

andHamp–/–mice exhibited similar weight

loss (Fig. 1A), indicative of comparable inflam-

mation and tissue damage. However, upon

removal of DSS,Hamp–/–mice exhibited per-

sistent weight loss, continued disruption of

186 10 APRIL 2020•VOL 368 ISSUE 6487 sciencemag.org SCIENCE

(^1) Jill Roberts Institute for Research in Inflammatory Bowel Disease (JRI), Weill Cornell Medicine, Cornell University, New York,
NY, USA.^2 Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell
Medicine, Cornell University, New York, NY, USA.^3 Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell
University, New York, NY, USA.^4 Université de Paris, INSERM U1016, Institut Cochin, CNRS UMR8104, 75014 Paris, France.
(^5) Laboratory of Excellence GR-Ex, Paris, France. (^6) Department of Environmental Medicine and Public Health, Icahn School of
Medicine at Mount Sinai, New York, NY 10029, USA.^7 Department of Molecular Medicine, University of Southern Denmark,
Odense, Denmark.^8 MD Anderson Cancer Center, Houston, TX, USA.^9 Sorbonne Université, Inserm, Centre de Recherche
Saint-Antoine, CRSA, AP-HP, Hôpital Saint Antoine, Service de Gastroenterologie, F-75012 Paris, France.^10 Department of
Oncology Research, Amgen Inc., Thousand Oaks, CA, USA.^11 Department of Pediatrics, Division of Gastroenterology and
Nutrition, Weill Cornell Medicine, Cornell University, New York, NY, USA.^12 Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford OX1 3PT, UK.^13 Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine,
Cornell University, New York, NY, USA.^14 Trinity College Dublin, Dublin, Ireland.
*These authors contributed equally to this work.†Present address: Department of Medicine, University of Padova and VIMM Veneto
Institute of Molecular Medicine, Padova, Italy.
‡Corresponding author. Email: [email protected] (G.F.S.); [email protected] (C.P.)
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