A Vascularized Human Organ Chip Reveals SARS-CoV-2 Susceptibility in Developmentally Guided Tissue Maturation.

Purpose: Stem cell-derived models offer traceable cell sources for studying tissue development and disease mechanisms. However, many such models have inherently immature or fetal-like phenotypes, limiting their relevance for mechanistic studies of specialized adult tissues. Clinical observations suggest a potential link between epithelial cells and their transit-amplifying progenitors in disease onset and viral tropism, but experimental validation is needed. This study aimed to develop mature visceral epithelial cells (podocytes) from human induced pluripotent stem (iPS) cells using a developmental approach and model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a vascularized microfluidic kidney-on-a-chip platform exhibiting in vivo-like tissue structure and function. Methods: Mature podocytes and vascular endothelial cells were differentiated from patient-specific human iPS cells by transitioning through distinct lineages that mimic human development. A personalized vascularized microphysiological platform containing the stem cell-derived kidney cells was engineered to model glomerular tissue and the kidney's blood filtration barrier. SARS-CoV-2 entry mechanisms and cell lineage marker expression were assessed at the transcriptome and proteome levels in the developing and mature cells and tissues. Results: The vascularized kidney-on-a-chip model revealed that susceptibility to SARS-CoV-2 particles was significantly higher in mature glomerular epithelium compared to less specialized derivatives and progenitor cells. The infection with SARS-CoV-2 also induced altered expression of cell lineage markers, with mature podocytes exhibiting distinct transcriptional responses linked to viral interacting epitopes and entry pathways. Conclusions: This study underscores the importance of using developmentally appropriate preclinical models to investigate disease mechanisms and potential therapeutic responses. These findings highlight the maturation-dependent susceptibility of specialized epithelial cells to viral infections, providing insights into organ-specific disease mechanisms and potential therapeutic strategies. These insights reinforce the need to refine preclinical model systems to closely align with human physiology and ensure the translational relevance of biomedical research. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-025-00851-4.