Adipose-derived Stem Cells and Wound Healing Are Progressively Impaired Long-term After Radiotherapy in Mice.

BACKGROUND

The pathogenesis of deterministic radiation damage is not clearly understood, but it has been reported that fibroinflammatory pathways are up-regulated. We hypothesized that the number of adipose-derived stem/stromal cells (ASCs) decline after radiotherapies, preventing normalization of fibrosis and angiogenesis, resulting in chronic radiation damages that progress over time.

METHODS

Dorsal skin of 8-week-old male BALB/cfC3H mice was irradiated with 10 Gy weekly for 4 weeks. At 1, 3, 6, 9, and 12 months after radiotherapy (n = 5, 5, 5, 5, and 4), tissue hemoglobin oxygen saturation, and time until epithelialization were evaluated. Skin biopsies were measured for thickness and CD34/isolectin stem/stromal cell count. Nonirradiated (NRT) controls were evaluated at each time point as well (n = 5 each).

RESULTS

Compared with NRT controls, time until epithelialization was significantly longer at 1 month (28 ± 3, < 0.01); not statistically different at 3 months (16 ± 2, = 0.32); and lengthened over time at 6 months (20 ± 2, = 0.21), 9 months (28 ± 2, < 0.01), and 12 months (26 ± 3, < 0.01), as did tissue oxygen saturation. The number of CD34/isolectin ASCs decreased over time, at 1 month (5.3 ± 1.3, = 0.01), 3 months (6.0 ± 1.4, = 0.03), 6 months (4.0 ± 0.8, < 0.01), 9 months (1.7 ± 0.5, < 0.01), and 12 months (0.3 ± 0.5, < 0.01). The subcutaneous fatty layer was significantly thinner at 3 months (116 ± 33, < 0.01), 6 months (147 ± 22, = 0.02), 9 months (52 ± 12, = 0.04), and 12 months (89 ± 19, = 0.04), but not at 1 month (141 ± 18, = 0.43).

CONCLUSIONS

After 6 months postirradiation, the number of ASCs continued to decline over time, accompanied by irreversible progression of fibrosis, atrophy, and ischemia, which resulted in impaired wound healing.