Irradiation Affects Adipose-Derived Stem Cells and Wound Healing Depending on Radiation Dose and Frequency.

Abstract

Radiation therapies are often associated with permanent devitalization in the surrounding tissue. The authors hypothesized that stem cells are damaged depending on each irradiation dose and frequency of fractionated radiotherapies, which results in impaired tissue function, including wound-healing capacity. Susceptibility of human adipose-derived stem cells (ASCs) to a single irradiation (0 to 10 Gy) was assessed in vitro. In vivo chronic radiation effects were also assessed on mouse dorsal skin ( n = 4 to 5) for 6 months after a total of 40 Gy irradiation (0 Gy as control) using 1 of 3 fractionated protocols (2 Gy daily for 20 days, 10 Gy weekly for 4 weeks, or 10 Gy monthly for 4 months). Oxygen partial pressure, oxygen saturation of hemoglobin, and dorsal skin viscoelasticity were measured periodically, and wound healing and tissue immunohistology were compared at 6 months. A single irradiation of cultured human ASCs resulted in a dose-dependent increase in cell death up to 2 Gy but with no further increases between 2 and 10 Gy. Most of the apoptotic ASCs were in the proliferation phase. Among the 3 in vivo irradiation protocols, the 2 Gy×20 group had the most severe chronic tissue damage (ie, skin dysfunction, subcutaneous atrophy, depletion of CD34 + stem cells) 6 months after the irradiation. Wound healing was also impaired most significantly in the 2 Gy×20 group. These results have important clinical implications for surgeons and radiotherapists in the timing of surgical interventions and the optimization of fractionation protocols. Irradiation damages stem cells depending on the radiation dose and frequency. Using the ultimately optimized protocol, surgeons can minimize the long-term functional deficits of radiated tissue without losing the anticancer efficacy of radiation therapy.