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Kidney Week

Abstract: TH-PO425

Study Sex Differences in Genetic Kidney Diseases Using Organoid Xenotransplantation Model

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Author

  • Xia, Yun, Nanyang Technological University, Singapore, Singapore, Singapore
Background

Chronic kidney disease (CKD) affects about 10% global population, with higher prevalence in women but faster progression in men. A deeper understanding of how the interplay between genetic sex and systemic sex hormones modifies human kidney disease constitutes a pivotal advancement toward precision medicine, which promises equitable benefits for women (including pregnant women), men, and transgender individuals alike. Despite mounting evidence that sex disparity must be taken into consideration in studying human kidney diseases and developing therapies, limited progress has been made due to the lack of suitable experimental models.

Methods

In this study, we harness this organoid xenotransplantation methodology to investigate the combined effects of genetic sex and systemic sex hormones on human genetic kidney disease. Single cell RNA-sequencing (scRNAseq), genetic perturbation, and pharmacological interference are employed to dissect the mechanism underlying sex differences manifested in different sex contexts.

Results

Induced pluripotent stem cells (iPSCs) derived from patients with autosomal recessive PKD (ARPKD) and autosomal recessive PKD (ARPKD) can be differentiated into kidney organoids. scRNAseq of kidney organoids detected enriched expression of androgen and estrogen receptors in the proximal tubule. Upon xenotransplantation into immunocompromised mice, kidney organoid grafts grown in male mice exhibited higher cystic index compared with the same patient iPSC derived kidney organoids grafted in female mice. Analyses of kidney organoid grafts revealed increased tubular injury, proliferation, and activation of androgen signalling in kidney organoids grafted in male host mice, compared with those grafted in female host mice. Genetic ablation or pharmacological inhibition of androgen receptor effectively inhibited cyst severity. Comparatively, genetic sex of the kidney organoid itself showed less impact on the severity of cystogenesis.

Conclusion

Organoid xenotransplantation model represents a feasible platform to comprehend sex disparity in human diseases, to distinguish the impact of genetic sex on human diseases from those imparted by systemic sex hormones, as well as to test candidate therapeutics targeting principal sex hormone signalling pathways for treating human diseases.