Single cell transcriptomic characterization of microtia reveals pathogenic dysregulation in previously unrecognized chondral stem/progenitor cell population

As one of most common birth defects worldwide, microtia results from auricular cartilage dysplasia and has unfortunate physical and psychological consequences for children. However, existing treatments have adverse outcomes and its pathogenesis is poorly understood. Since characterization of cell type composition and function in normal auricular cartilage can increase our understanding of microtia, we conducted single-cell transcriptomic profiling for 47,969 human auricular cartilage cells obtained from three microtia and six normal control (NC) samples. Comprehensive bioinformatic analysis identified seven cartilage-related cell subtypes belonging to the chondral and stromal lineages. We also found age-associated changes in gene expression shared across all subtypes in the chondral lineage of NC. Additionally, we revealed the previously unrecognized chondral stem/progenitor cells (CSPCs) that were mainly located in the chondrium and might have the potential for directed chondrogenic differentiation. Our results showed that dysregulation of SOX8 and EGR1 in CSPCs of microtia impaired cartilage development and enhanced oxidative stress response, respectively. These findings shed light on the potential mechanisms of microtia pathogenesis and offer novel avenues for the development of treatment strategies Single-cell mRNA sequencing of human auricular cartilage cells obtained from three microtia and six normal control (NC) samples.