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Progranulin is a mediator of the wound response

Abstract

Annually, 1.25 million individuals suffer burns in the United States and 6.5 million experience chronic skin ulcers, often from diabetes, pressure or venous stasis1. Growth factors are essential mediators of wound repair1,2, but their success as therapeutics in wound treatment has, so far, been limited1,2. Therefore, there is a need to identify new wound-response regulatory factors, but few have appeared in recent years1,2. Progranulin3 (also called granulin or epithelin precursor4, acrogranin5 or PC-derived growth factor6) is a growth factor involved in tumorigenesis6,7,8,9,10,11 and development12,13. Peptides derived from progranulin have been isolated from inflammatory cells14, which led to suggestions that progranulin gene products are involved in the wound response10,14, but this remains undemonstrated. We report that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels and fibroblasts in the wound. It acts directly on isolated dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures. Progranulin is, therefore, a probable wound-related growth factor.

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Figure 1: The expression of progranulin mRNA is induced in wounded skin.
Figure 2: Progranulin promotes the wound response.
Figure 3: Progranulin stimulates proliferation and migration of isolated dermal fibroblasts and endothelial cells, and tubule formation by endothelia.

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Acknowledgements

We thank A. Mah for assistance with the in situ hybridization and W. Powell for performing neutrophil chemoattractant assays. This work was supported by a grant from the Canadian Institutes of Health Research to A.B. (MT-011397), by studentships from the Research Institute of the Royal Victoria Hospital to Z.H. and C.H.P.O., by NIH grant to J.H. (CA71023) and by a grant from The University of Georgia Research Foundation.

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Correspondence to Andrew Bateman.

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He, Z., Ong, C., Halper, J. et al. Progranulin is a mediator of the wound response. Nat Med 9, 225–229 (2003). https://doi.org/10.1038/nm816

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