A gel carrying the gene for the enzyme TKT accelerated wound healing in diabetic mice and pigs

A gel carrying the gene for the enzyme TKT accelerated wound healing in diabetic mice and pigs

A study published on 17 October in Nature Communications examined how diabetes impairs the restoration of blood supply to wounds. The authors linked this impairment to a deficiency of the enzyme TKT in macrophages and tested a hydrogel that delivers a plasmid, a circular DNA molecule carrying the TKT gene, into these cells.

Skin repair requires new small blood vessels to supply the tissue with oxygen and nutrients. Macrophages contribute to this process. These immune cells help wounds progress from the initial inflammatory phase to repair. The authors investigated why this support weakens in diabetes, focusing on TKT, an enzyme involved in cellular metabolism and protection against oxidative stress.

TKT levels were lower in macrophages from wounds in diabetic mice. The authors also observed lower TKT levels in samples of chronic wounds from people with diabetes compared with acute traumatic wounds from people without diabetes. To test the enzyme's role, the researchers deleted TKT in mouse myeloid cells, a group that includes macrophages. Wounds in these animals closed more slowly, with less formation of new dermal connective tissue and collagen.

In cell culture under high-glucose conditions, macrophages lacking TKT were less able to support the cells that line blood vessels. These cells proliferated and migrated more slowly and formed fewer vessel-like tubes in a laboratory assay. High glucose reduced TKT levels, and TKT deficiency increased AGEs–RAGE signaling: molecules modified by excess sugar activate the RAGE receptor and sustain inflammation. Inhibiting RAGE partially restored the vessel-lining cells' ability to proliferate, migrate, and form vessel-like tubes.

For local delivery, the researchers loaded the plasmid carrying the TKT gene into copper-zinc nanoparticles, coated them with mannose to favor uptake by macrophages, and incorporated them into a hydrogel. By day 14, wounds in diabetic mice treated with this hydrogel had closed by 90,06% of their original area, compared with 72,37% for the carrier without the plasmid. In diabetic pigs with full-thickness wounds measuring 2 × 2 centimeters, the hydrogel accelerated wound closure over 18 days, increased TKT levels in macrophages, and increased the density of small blood vessels.