Unveiling Tissue-Specific Transcriptional Adaptations in iPSC-Derived Fibroblasts via Co-Culture Systems

Induced pluripotent stem cell-derived fibroblasts (iFBs) are promising tools for autologous disease modelling, but their ability to replicate tissue-specific fibroblast characteristics remains unclear. Fibroblasts are highly heterogeneous, with distinct subtypes playing critical roles in tissue function and organ integrity. This study investigates whether iFBs can acquire tissue-specific transcriptional profiles through co-culture with cells found in the skin (keratinocytes), heart (cardiomyocytes), gut (intestinal) and lung (bronchial epithelial Transcriptomic analyses revealed that iFBs exhibit transcriptional plasticity, adopting molecular phenotypes aligned with their co-culture environment across all three germ layers.Additionally, paracrine signalling induced tissue-specific changes in indirectly co-cultured iFBs, though these adaptations were transient without sustained interaction.These findings demonstrate the potential of iFBs to mimic native fibroblast behaviour but also highlight the need for validation in complex tissue models to account for variability in iPSC differentiation and functional stability. By providing evidence of tissue-specific plasticity, this study supports the utility of iFBs in developing physiologically relevant in vitro systems.