Keratinocyte-Secreted Heat Shock Protein-90alpha: Leading Wound Reepithelialization and Closure

Significance: Delayed and nonhealing wounds pose a health, economic, and social problem worldwide. For decades, the conventional wisdom pointed to growth factors as the driving force of wound healing and granted them a center stage for therapeutic development. To date, few have obtained US FDA approvals or shown clinical effectiveness and safety. Critical Issue: Wound closure is the initial and most critical step during wound healing. Closing chronic wounds to shut down continued infection is the primary and likely the only achievable goal at the clinic in the foreseeable future. The critical question here is to identify the factor(s) in wounded tissues that drives the initial wound closure. Recent Advances: We made an unexpected discovery of the secreted form of heat shock protein-90alpha (Hsp90 alpha) for promoting skin cell motility, reepithelialization, and wound closure. Secreted Hsp90 alpha possesses unique properties to remain functional under the hostile wound environment that compromises conventional growth factors' effectiveness. Through the common lipoprotein receptor-related protein-1 cell surface receptor and activation of the Akt signaling pathway, topical application of human recombinant Hsp90 alpha protein greatly accelerates excision, burn, and diabetic skin wound closure in rodent and porcine models. Future Directions: In almost all cells, the 2-3% of their total proteins (similar to 7,000 per cell) are Hsp90 (alpha and beta), a long unraveled puzzle. Our new finding of Hsp90 secretion in wounded tissues suggests that the stockpile of Hsp90 alpha by all cells is to rapidly supply the need for extracellular Hsp90 alpha to repair damaged tissues. We propose that keratinocytes at the wound edge secrete Hsp90 alpha that leads the reepithelialization process to close the wound.