Insulin-like growth factor 2 as a driving force for exponential expansion and differentiation of the neonatal thymus

Like all organs, the thymus grows in size and function rapidly during development, but this growth 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 that IGF2 activity promotes a cortical thymic epithelial cell-specific proliferation and is tightly regulated at the thymic growth transition. Bulk RNA-seq of human thymi across the transition also revealed that IGF2 drives thymic expansion, suggesting an evolutionarily conserved role. Our study highlights the role of fibroblast-derived IGF2 in promoting cortical thymic epithelial cell proliferation and differentiation, resulting in early thymic expansion that is followed by downregulation to establish homeostasis.