Keratinocyte-secreted Hsp90a-containing Exosomes Are A Driving Force Of Wound Closure
University of Southern California, Los Angeles, CA, USA.
Background: Defects in tissue repair and wound healing in humans pose clinical, economic and social problems worldwide. During the entire year-long process of wound healing, only the initial period of the wound closure phase has animal models for research and has been the focus for therapeutic development. Despite decades of laboratory studies and clinical trials, few of the previous drug candidates have advanced to approval for treatment of human wounds. To overcome this deadlock, we propose that it is crucial to identify the natural "driver genes" for wound closure as new drug candidates. Methods: Acute, burn and diabetic skin wound models in mice and pigs Results: We found that when skin is injured, there is a massive deposition of heat shock protein 90alpha (Hsp90α) protein into the wound bed via keratinocyte-secreted exosomes. Although Hsp90α does not contain any membrane-anchoring motif, it is located on the surface of secreted exosomes, enabling it to bind to the LRP-1 receptor on all skin cell types to promote wound closure. Through binding to LRP-1 receptor, secreted Hsp90α exerts two critical functions to support wound closure: i) preventing cells at the wound edge undergoing hypoxia-triggered apoptosis and ii), thereafter, stimulating the cells to migrate and re-epithelialize the wound. When these two functions of keratinocyte-secreted Hsp90α were inhibited, wound closure failed to complete in a timely fashion. Finally, topical application of a recombinant Hsp90α protein that mimics keratinocyte-secreted Hsp90α, promotes wound closure in traumatic/excisional, diabetic and burn wounds in both murine and porcine models. Conclusions: A newly identified therapeutic entity of human Hsp90α, a 115-amino acid peptide, has potential as a treatment of both acute and chronic skin wounds in humans.
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