Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 290, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3010228
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Funding
- NIH grants from the National Institute of Dental and Craniofacial Research [RO1 DE021215, DE021104]
- F. M. Kirby Foundation
- G. Harold and Leila Y. Mathers Foundation
- Wistar Cancer Center grant from the National Cancer Institute, NIH [P30 CA010815]
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Whereas amphibians regenerate lost appendages spontaneously, mammals generally form scars over the injury site through the process of wound repair. The MRL mouse strain is an exception among mammals because it shows a spontaneous regenerative healing trait and so can be used to investigate proregenerative interventions in mammals. We report that hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a central molecule in the process of regeneration in adult MRL mice. The degradation of HIF-1 alpha protein, which occurs under normoxic conditions, is mediated by prolyl hydroxylases (PHDs). We used the drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), a PHD inhibitor, to stabilize constitutive expression of HIF-1 alpha protein. A locally injectable hydrogel containing 1,4-DPCA was designed to achieve controlled delivery of the drug over 4 to 10 days. Subcutaneous injection of the 1,4-DPCA/hydrogel into Swiss Webster mice that do not show a regenerative phenotype increased stable expression of HIF-1 alpha protein over 5 days, providing a functional measure of drug release in vivo. Multiple peripheral subcutaneous injections of the 1,4-DPCA/hydrogel over a 10-day period led to regenerative wound healing in Swiss Webster mice after ear hole punch injury. Increased expression of the HIF-1 alpha protein may provide a starting point for future studies on regeneration in mammals.
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