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Transforming Growth Factor (TGF)-Stimulated Secretion of HSP90: Using the Receptor LRP-1/CD91 To Promote Human Skin Cell Migration against a TGFβ-Rich Environment during Wound Healing ^,

Chieh-Fang Cheng,¹ Jianhua Fan,¹ Mark Fedesco,¹ Shengxi Guan,¹ Yong Li,^1, Balaji Bandyopadhyay,^1, Alexandra M. Bright,¹ Dalia Yerushalmi,¹ Mengmeng Liang,¹ Mei Chen,¹ Yuan-Ping Han,² David T. Woodley,^1* and Wei Li^1*

Department of Dermatology and Norris Comprehensive Cancer Center,¹ Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California 90033²

Received 17 July 2007/ Returned for modification 17 September 2007/ Accepted 27 February 2008

Jump-starting and subsequently maintaining epidermal and dermal cell migration are essential processes for skin wound healing. These events are often disrupted in nonhealing wounds, causing patient morbidity and even fatality. Currently available treatments are unsatisfactory. To identify novel wound-healing targets, we investigated secreted molecules from transforming growth factor (TGF)-stimulated human keratinoytes, which contained strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein 90 (hsp90) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGF causes rapid membrane translocation and subsequent secretion of hsp90 via the unconventional exosome pathway in the cells. Secreted hsp90 promotes both epidermal and dermal cell migration through the surface receptor LRP-1 (LDL receptor-related protein 1)/CD91. The promotility activity resides in the middle domain plus the charged sequence of hsp90 but is independent of the ATPase activity. Neutralizing the extracellular function of hsp90 blocks TGF-induced keratinicyte migration. Most intriguingly, unlike the effects of canonical growth factors, the hsp90 signaling overrides the inhibition of TGFβ, an abundant inhibitor of dermal cell migration in skin wounds. This finding provides a long-sought answer to the question of how dermal cells migrate into the wound environment to build new connective tissues and blood vessels. Thus, secreted hsp90 is potentially a new agent for wound healing.

Published ahead of print on 10 March 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Plastic Surgery, Xijing Hospital, FMMU, Xian, China.

Present address: Department of Regenerative Medicine, Reliance Life Sciences Pvt. Ltd., Mumbai, India.