Macrophage Wnt7b is critical for kidney repair and regeneration

doi:10.1073/pnas.0912228107

Macrophage Wnt7b is critical for kidney repair and regeneration

^aLaboratory of Inflammation Research, Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
^bDepartment of Medicine, National Taiwan University Hospital, Tipei 100, Taiwan;
^cVisual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229;
^dDepartment of Ophthalmology, University of Cincinnati, Cincinnati, OH 45229;
^eDepartment of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105;
^fDepartment of Internal Medicine, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
^gDepartment of Molecular and Developmental Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461; and
^hDepartment of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

↵²Present address: Nephrology Department, 2nd Teaching Hospital of Harbin Medical University, 345 Xuefu Road, Nangang District, Harbin 150086, China.

Edited* by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved January 7, 2010 (received for review October 23, 2009)
↵¹S.-L.L. and B.L. contributed equally to this work.

Abstract

Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. Furthermore, when Wnt7b is somatically deleted in macrophages, repair of injury is greatly diminished. Finally, injection of the Wnt pathway regulator Dkk2 enhances the repair process and suggests a therapeutic option. Because Wnt7b is known to stimulate epithelial responses during kidney development, these findings suggest that macrophages are able to rapidly invade an injured tissue and reestablish a developmental program that is beneficial for repair and regeneration.

Footnotes

³To whom correspondence may be addressed. E-mail: richard.lang{at}cchmc.org or jduffield{at}rics.bwh.harvard.edu.
Author contributions: S.-L.L., R.A.L., and J.S.D. designed research; S.-L.L., B.L., S.R., E.-J.Y., T.E.H., B.T.N., H.P., and J.S.D. performed research; S.-L.L., L.C., J.J.Z., T.J.C., J.W.P., A.P.M., R.A.L., and J.S.D. contributed new reagents/analytic tools; S.-L.L., B.L., R.A.L., and J.S.D. analyzed data; and A.P.M., R.A.L., and J.S.D. wrote the paper.
Conflict of interest statement: R.A.L. and J.S.D. have submitted a patent application for the use of Dkk2 and other Wnt agonists in regeneration.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/cgi/content/full/0912228107/DCSupplemental.