Insulin-like growth factor 2 (IGF2) as a driving force of exponential expansion in neonatal thymus

Like all organs, the thymus grows in size and function rapidly during development, which comes to a halt after birth. However, the molecular mechanisms behind such a transition in the thymus remain obscure. Using single-cell RNA sequencing (scRNA-seq) of the murine thymic stroma, we identified that major transcriptomic changes occur in the endothelium and mesenchyme across the transition to homeostasis. Differentially expressed gene and intercellular network analyses of temporally resolved scRNA-seq data revealed fibroblast-derived insulin-like growth factor 2 (IGF2) as a candidate driving neonatal thymic expansion. We demonstrated IGF2 activity promotes a cortical TEC-specific proliferation and is tightly regulated at the thymic growth transition. Bulk RNA-seq of human thymi across the transition also revealed IGF2 to drive thymic expansion, suggesting an evolutionarily conserved role. Our study highlights the role of a fibroblast-derived IGF2 in promoting cTEC proliferation, resulting in early thymic expansion that is followed by down-regulation to establish homeostasis. Overall design: For our time-series single-cell RNA sequencing, we used 3 thymi per library. Our merged scRNAseq dataset contains 3-day-old (3 Foxn1+/+ males, 3 Foxn1lacZ/lacZ males, 2 Foxn1+/+ females, 2 Foxn1lacZ/lacZ females), 7-day-old (2 Foxn1+/+ males, 3 Foxn1lacZ/lacZ males), 14-day-old (2 Foxn1+/+ males, 2 Foxn1lacZ/lacZ males, 2 Foxn1+/+ females, 2 Foxn1lacZ/lacZ females). 30-day-old (2 Foxn1+/+ males, 3 Foxn1lacZ/lacZ males) datasets are available in a separate manuscript, Xiao*, Kang* et al. (2025). GSE264402.