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Science 338 (6103): 108-113

Copyright © 2012 by the American Association for the Advancement of Science

Wnt5a Potentiates TGF-β Signaling to Promote Colonic Crypt Regeneration After Tissue Injury

Hiroyuki Miyoshi,1 Rieko Ajima,2,* Christine T. Luo,1 Terry P. Yamaguchi,2,{dagger} Thaddeus S. Stappenbeck1,{dagger}

Abstract: Reestablishing homeostasis after tissue damage depends on the proper organization of stem cells and their progeny, though the repair mechanisms are unclear. The mammalian intestinal epithelium is well suited to approach this problem, as it is composed of well-delineated units called crypts of Lieberkühn. We found that Wnt5a, a noncanonical Wnt ligand, was required for crypt regeneration after injury in mice. Unlike controls, Wnt5a-deficient mice maintained an expanded population of proliferative epithelial cells in the wound. We used an in vitro system to enrich for intestinal epithelial stem cells to discover that Wnt5a inhibited proliferation of these cells. Surprisingly, the effects of Wnt5a were mediated by activation of transforming growth factor–β (TGF-β) signaling. These findings suggest a Wnt5a-dependent mechanism for forming new crypt units to reestablish homeostasis.

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2 Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.

* Present address: Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871 Japan.

{dagger} To whom correspondence should be addressed. E-mail: stappenb{at} (T.S.S.); yamagute{at} (T.P.Y.)

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