A radiation biological effect of a given dose generally decreases with decreasing radiation dose rate, which is known as a “dose-rate effect”. The dose-rate effect demonstrated by many cellular and animal studies. Additionally, recent epidemiological study in high background radiation area in Kerala, India showed that cancer incidence did not increase with increasing cumulative dose (Jayalekshmi et al. Radiat Environ Med 2021). Tissue stem cells have been considered as a target of radiation-induced carcinogenesis. Radiation biological effect could be reduced if damaged stem cells are eliminated by stem cell competition. ICRP described that stem cell competition at the tissue level leaves an ample possibility for a dose-rate effective factor (DREF) value larger than unity, as in the case of the current dose and dose-rate effective factor (DDREF) value (ICRP Publication 131).
Cells expressing Lgr5 are one of the major components of intestinal stem cells. Intestinal organoids are three-dimensional cultured tissue model generated from intestinal stem cells. To evaluate a radiation-induced stem cell competition, we established a quantitative method using mixed-organoid derived from two independent fluorescent protein-expressing Lgr5 stem cells, which one of stem cells were irradiated, for mimicking heterogeneous exposure under low-dose-rate irradiation. The organoid-forming potential (OFP) is one of the indices of the abilities of self-renewal, proliferation, and differentiation of stem cells. We found that irradiated stem cells exhibited a growth disadvantage in the mixed organoid, whereas the OFP of irradiated cells per se did not decrease significantly from that of non-irradiated cells. Additionally, we constructed a mathematical model to assess stem cell competition under low-dose-rate irradiation condition. In our model, a stem cell pool, containing a constant number of cells, was assumed, and changed through transition and turnover event. The intact cells turned into damaged cells through transition event which was assumed as the effect of radiation exposure. In the turnover event, a single cell was divided, and a single cell was eliminated from the stem cell pool. The probability of cell division and elimination depended on the properties of cells. The properties of damaged cells were different from that of intact cells. Under very low-dose-rate conditions, the radiation damage was suppressed when the damaged cells were less reproductive and tended to be eliminated compared to the intact cells.
These results suggest the radiation-induced stem cell competition can be occurred in the intestine, and the stem-cell competition plays an important role in suppress carcinogenesis under low-dose-rate irradiation condition.
Keywords: Stem cell competition; Dose-rate effect; DDREF; Carcinogenesis; Organoid