HOXA3 Upregulation Accelerates Wound Healing in Aged Mice
Researchers here show that a gene therapy approach to upregulation of HOXA3 can accelerate wound healing in old mice. HOXA3 regulates a number of different processes related to tissue regeneration, though it is unclear as to which of these is more important in producing the observed outcome. It is worth noting that adjusting macrophage polarization to the M2 state is one of the mechanisms in play. Macrophages can adopt a range of states known as polarizations, where the more inflammatory M1 polarization is more suited to hunting down pathogens than participating in tissue regeneration. The more inflammatory environment of aged tissues may bias macrophages towards M1 and away from the desired M2 state. Methods of adjusting macrophage polarization are under investigation by a broad range of research groups as a potential way to reduce unresolved inflammatory signaling and improve the interaction of these innate immune cells with tissues in disease states and aging.
Chronic wounds are characterized by a persistent, hyper-inflammatory environment that prevents progression to regenerative wound closure. Such chronic wounds are especially common in diabetic patients, often requiring distal limb amputation, but occur in non-diabetic, elderly patients as well. Induced expression of HoxA3, a member of the Homeobox family of body patterning and master regulatory transcription factors, has been shown to accelerate wound closure in diabetic mice when applied topically as a plasmid encased in a hydrogel.
The mechanisms underlying the wound healing ability of HOXA3 has been preliminarily investigated. Macrophages transduced with HOXA3 promoted M2 polarization compared to controls. Furthermore, HOXA3 treatment mobilized and recruited endothelial progenitor cells while attenuating inflammatory pathways when compared to control mice and HOXA3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic myeloid cells that stimulate neovascularization.
We now provide independent replication of those foundational in vivo diabetic wound closure studies, observing 16% faster healing (3.3 mm wounds vs 3.9 mm wounds at Day 9 post original injury of 6 mm diameter) under treatment with observable microscopic benefits. We then expand upon these findings with minimal dose threshold estimation of 1 μg HoxA3 plasmid delivered topically at a weekly interval. Furthermore, we observed similarities in natural wound healing rates between aged non-diabetic mice and young diabetic mice, which provided motivation to test topical HoxA3 plasmid in aged non-diabetic mice. We observed that HoxA3 treatment achieved complete wound closure (0 mm diameter) at 2 weeks whereas untreated wounds were only 50% closed (3 mm wound diameter). We did not observe any gross adverse effects macroscopically or via histology in these short studies. Whether as a plasmid or future alternative modality, topical HoxA3 is an attractive translational candidate for chronic wounds.