A Human Precision Cut Kidney Slice Platform for Studying Glomerular Biology and Therapeutic Responses
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Introduction
Short term human precision cut kidney slice cultures (PCKS) represent a tractable experimental that contains mature kidney cell types within their native anatomic context and that can be manipulated in vitro . In this study, we employ genomic tools to analyze the PCKS response to culture conditions and their suitability for study of glomerular disease biology.
Methods
The impact of culture medium and oxygenation on PCKS viability and gene expression was explored using spatial transcriptomics and traditional histologic approaches. The biological response of PCKS to IFNγ stimulation and signaling suppression by the JAK1/2 inhibitor baricitinib were also explored.
Results
A genome wide atlas of glomerular and tubulointerstitial gene expression patterns was generated from PCKS cultured in different media and oxygenation conditions and at various timepoints in culture. IFNγ induced APOL1 gene and protein expression in glomeruli, which could be suppressed by baricitinib. Expression changes were reproducible in PCKS derived from multiple donors.
Conclusions
PCKS are reproducibly responsive to IFNγ stimulation, which will allow dissection of APOL1 mediated glomerular disease mechanisms in a human tissue model system. Spatial transcriptomic profiling of tissue responses helps to tailor culture medium/oxygenation to optimize the PCKS system to address specific biological questions.
Translational Statement
Human kidney slice cultures preserve mature cells within their native tissue architecture, enabling direct study of disease mechanisms and drug responses in human tissue. Combining this platform with spatial transcriptomics identified reproducible tissue responses to the inflammatory cytokine IFNγ. It also uncovered expected and unanticipated effects of baricitinib, a clinically approved medication. This kidney slice approach could help prioritize therapies for glomerular diseases, including APOL1-associated kidney disease, and identify potential adverse effects before patient trials. This platform offers a fully human tissue system for preclinical testing of candidate therapies and assessment of their molecular effects within the native kidney microenvironment.
