A human iPSC-derived kidney-liver organ-on-a-chip platform for modeling inter-organ crosstalk.

Abstract

The liver and kidneys are essential for drug metabolism and clearance and are highly sensitive to toxicity. Most <i>in vitro</i> models assess these organs in isolation, limiting the study of inter-organ interactions. Here, an induced pluripotent stem cell (iPSC)-derived kidney-liver organ-on-a-chip model was developed that co-cultured hepatocyte-like cell (HLC) organobodies and proximal tubular-like cells (PTL) under microfluidic flow. In parallel, a PTL-HepaRG spheroid co-culture model was established to investigate bioactivation of the prodrug ifosfamide. Co-culture induced distinct transcriptional responses in PTL and HLC, as revealed by gene set enrichment analysis. In PTL, co-culture with HepaRG enriched signaling and cell polarity pathways, while co-culture with HLC enhanced metabolic and transport-related programs. In HLC, co-culture with PTL affected intermediary metabolism, lipid processing, redox regulation, and plasma protein synthesis. The PTL-HepaRG model demonstrated bioactivation of ifosfamide into metabolite chloroacetaldehyde, highlighting the utility of these systems for studying human-relevant kidney-liver interactions and drug metabolism <i>in vitro</i>. However, the concentration of chloroacetaldehyde was too low to cause adverse effects in the renal tissue in the current setup.