LGR5+ Intestinal Stem Cells Display Sex-Dependent Radiosensitivity

Author:

Zitter Ryan C.1ORCID,Chugh Rishi Man1ORCID,Bhanja Payel1,Kimler Bruce F.1ORCID,Saha Subhrajit12ORCID

Affiliation:

1. Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA

2. Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA

Abstract

Tissue radiosensitivity plays a critical role in the overall outcome of radiation therapy. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data have suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In a mouse model of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity were not dependent on sex hormones, as we demonstrated similar sex-specific radiosensitivity differences in pre-pubescent mice. In an ex vivo study, we found that patient-derived intestinal organoid (PID) from males showed higher sensitivity to radiation compared to females as evident from loss of budding crypts, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation-induced upregulation of mitochondrial oxidative metabolism in males compared to females, a possible mechanism for radiosensitivity differences.

Funder

NIH

Publisher

MDPI AG

Subject

General Medicine

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Intestinal organ chips for disease modelling and personalized medicine;Nature Reviews Gastroenterology & Hepatology;2024-08-27

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