Hedgehog-interacting protein orchestrates alveologenesis and protects against bronchopulmonary dysplasia and emphysema

作者：D. Ye, Shiyun Feng, Xinguo Yang, Yanjing Su, Jing Zhang, Haixin Feng, Minqi Zhou, Bin Zhou, Lihui Duan, Tien Peng, Chaoqun Wang · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adu2958 · 被引用次数：8 · 研究领域：Neonatal Respiratory Health Research、Congenital Diaphragmatic Hernia Studies、Ethics and Legal Issues in Pediatric Healthcare

Most of the lung’s gas-exchange surface forms during alveologenesis and its disruption causes bronchopulmonary dysplasia (BPD) in infants, characterized by alveolar simplification and myofibroblast accumulation. BPD also increases the risk of adult emphysema, marked by alveolar loss. Despite this connection, mechanisms linking these conditions and effective treatments are still lacking. We identify hedgehog-interacting protein ( HHIP ), associated with both BPD and emphysema, as a critical regulator of alveologenesis. During this process, Hhip -expressing cells expanded, accompanied by hedgehog (Hh) signaling inhibition and myofibroblast transition. Stromal-specific Hhip deletion led to hyperactivation of Hh-IGF1 signaling axis, causing persistent SMA + myofibroblasts and epithelial stem/progenitor cell senescence. Hyperactivation of this pathway was also observed in human BPD and hyperoxia-induced BPD models. Early Hhip deficiency resulted in adult emphysema with myofibroblast accumulation. We developed a therapeutic Fc-fused HHIP protein that mitigated BPD in neonatal mice and prevented adult emphysema. These findings establish HHIP as a critical regulator of alveologenesis and a therapeutic target for BPD and emphysema.