LGR5+ Intestinal Stem Cells Display Sex Dependent Radiosensitivity

Area of Science:

• Oncology
• Radiation Biology
• Gastroenterology

Background:

• Radiosensitivity is crucial for radiation therapy outcomes.
• Intestinal radiation toxicity remains a clinical challenge.
• Sex-specific differences in radiotherapy outcomes are suggested but understudied.

Approach:

• Investigated sex-specific radiosensitivity in mouse models and human intestinal organoids.
• Assessed oxidative stress, injury, and Lgr5+ intestinal stem cell response to irradiation.
• Analyzed transcriptomic data to identify underlying molecular mechanisms.

Key Points:

• Male mice showed increased oxidative stress and intestinal injury post-irradiation compared to females.
• Male Lgr5+ intestinal stem cells exhibited greater sensitivity to radiation-induced toxicity.
• Human patient-derived intestinal organoids from males were more sensitive to irradiation than females.
• Sex-specific radiosensitivity differences persisted in pediatric mice, independent of sex hormones.

Conclusions:

• Demonstrated significant sex-specific differences in intestinal epithelial radiosensitivity.
• Identified increased oxidative stress and mitochondrial metabolism in males as a potential mechanism.
• Findings highlight the importance of considering sex in radiation therapy for gastrointestinal malignancies.