Insulin-like growth factor 2 (IGF2) as a Foxn1-independent driving force of exponential expansion in neonatal thymus. Insulin-like growth factor 2 (IGF2) as a Foxn1-independent 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: Bulk RNA sequencing was performed on thymus tissues from human donors aged 3 days to 14 years.

与所有器官一致，胸腺在发育阶段会经历体积与功能的快速增长，该进程在出生后即停止。然而，介导胸腺发生这一转变的分子机制至今仍不明晰。本研究针对小鼠胸腺基质开展单细胞RNA测序（single-cell RNA sequencing, scRNA-seq），发现在向稳态过渡的过程中，内皮细胞与间充质细胞出现了显著的转录组变化。对具有时间分辨率的scRNA-seq数据进行差异表达基因与细胞间网络分析后，我们鉴定出成纤维细胞来源的胰岛素样生长因子2（IGF2）为驱动新生胸腺扩张的候选靶点。实验证实，IGF2的活性可促进皮质胸腺上皮细胞（cortical thymic epithelial cell, cTEC）的特异性增殖，且在胸腺生长转变节点受到严格调控。对年龄覆盖3天至14岁的人类供体胸腺组织开展的批量RNA测序（bulk RNA-seq）结果同样显示，IGF2可推动胸腺扩张，提示其作用在进化上具有保守性。本研究阐明了成纤维细胞来源的IGF2在促进cTEC增殖中的关键作用：该因子可介导早期胸腺扩张，随后其表达会被下调以建立胸腺稳态。整体实验设计：对年龄介于3天至14岁的人类供体胸腺组织实施了批量RNA测序。