Can Harnessing a Tumor’s Power Help Heal Diabetic Foot Ulcers?

Normal macrophages derived from mouse bone marrow can gain a new set of pro-regenerative functions after co-culture with tumor-associated macrophages, and when transferred to the wound bed in diabetic mice, these cells potently induce cell proliferation, resolve inflammation, and orchestrate vasculature in the typically non-healing wounds.

Scientists may have found a way to train healthy immune cells to accelerate diabetic wound healing. 

The findings appear in EMBO Molecular Medicine.

Diabetic foot ulcers result in an amputation every 30 seconds on average. One of the fundamental reasons behind the non-healing status of  these ulcers, compared with common cutaneous wounds, is the dysfunction of macrophages. These cells change their functions to coordinate wound healing in different stages but fail to do so in diabetes.

The collaborative team, led by Professor Chunming Wang at the University of Macau and Professor Lei Dong at Nanjing University, were inspired by tumor-associated macrophages, which play essential roles in driving tumor development by secreting factors that promote blood vessel formation and inhibit immune attack. They realized that such features perfectly fulfil the requirements for diabetic wound healing. They hypothesized that tumor-associated macrophages could ‘pass on’ these features to non-tumor macrophages through co-culture.

They found that normal macrophages derived from mouse bone marrow can gain a new set of pro-regenerative functions after co-culture with tumor-associated macrophages. When transferred to the wound bed in diabetic mice, these cells potently induce cell proliferation, resolve inflammation, and orchestrate vasculature in the typically non-healing wounds. Further, gene analytical tools including single-cell RNA sequencing showed that these tumor-associated macrophage-educated macrophages are distinct from known phenotypes (typically simplified as M1 or M2 in biological terminology). In short , these cells exhibit unique skills after training that appropriately fulfill the demands of diabetic wounds.

The team identified the multiple factors that equip normal macrophages with these reparative capabilities and reconstituted a nine-factor cocktail which was tested on human monocytes, leading to a desirable outcome. Furthermore, this test eliminates any tumor-derived components, representing the imminent translational potential for a clinical trial.

PHOTO CAPTION: SCIENTISTS FROM MACAU AND NANJING DEVELOP A TUMOUR-INSPIRED STRATEGY FOR PROMOTING DIABETIC WOUND HEALING. ADOPTIVE TRANSFER OF THE ENGINEERED CELLS (TAMEM) RESTORED BLOOD VASCULATURE IN MOUSE DIABETIC WOUNDS SIMILAR TO UNWOUNDED STATUS vi