Developing a sex-specific model of acute kidney injury using induced pluripotent stem cell-derived proximal tubule cells

Tidmore, Josephine 2025. Developing a sex-specific model of acute kidney injury using induced pluripotent stem cell-derived proximal tubule cells. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Acute kidney injury (AKI) is a leading cause of morbidity and mortality worldwide. Following injury, the kidney may undergo adaptive repair, restoring function, or maladaptive repair, progressing toward chronic kidney disease. The factors governing this transition remain poorly understood, and biological sex has recently emerged as an important determinant of disease outcome. While in vitro and in vivo studies have provided insights into AKI, these findings have yet to translate into effective therapies. Advanced human models that recapitulate kidney physiology are therefore needed. This thesis investigates human induced pluripotent stem cell-derived proximal tubule cell (iPSC-PTC) organoids, generated from male and female iPSC lines, as a tractable platform for modelling kidney function and injury. A scalable spheroid-based differentiation protocol was tested in two iPSC lines, revealing line-specific differences in temporal gene expression and proximal tubule maturation. NOSN6-derived organoids exhibited higher and sustained nephron progenitor marker expression, formed discrete tubule-like structures, and showed partial polarisation, whereas KOLF2-derived organoids displayed limited organisation and reduced maturation. Organoid exposure to oxidative stress (H2O2) produced reproducible, concentration-dependent injury responses, demonstrating functional utility for modelling proximal tubule damage. Complementary singlenucleus RNA sequencing and spatial transcriptomics in male and female postnatal mouse kidneys delineated dynamic proximal tubule states, revealing sex-specific transcriptional programmes in the maturing nephron. Together, this work shows that iPSC-PTC organoids recapitulate key aspects of proximal-tubule development and provide a scalable, controllable model for probing injury mechanisms.

Item Type:	Thesis (MPhil)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	2 April 2026
Last Modified:	02 Apr 2026 09:09
URI:	https://orca.cardiff.ac.uk/id/eprint/186042

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