加州大学顾名夏团队宣布他们揭示了NTRK2亚型再平衡促进支气管肺发育不良的血管再生。2025年12月24日出版的《细胞—干细胞》杂志发表了这项成果。

通过从人BPD肺中分离的内皮细胞的多组学分析，该研究团队发现了以神经营养受体酪氨酸激酶2 （NTRK2）为标志的一般毛细血管内皮细胞（gCaps）的扩张。值得注意的是，该团队发现了一个控制gCap再生的关键异构体开关。全长NTRK2 （NTRK2-FL）促进了高氧损伤后gCap的修复，而RBFOX2介导的NTRK2-FL剪切成截断异构体（NTRK2-T1）导致适应不良反应和持续的肺泡简化。在高氧小鼠中，恢复NTRK2-FL主题化脂质纳米颗粒递送的mRNA促进了血管类器官的血管生成，逆转了肺泡简化。这些发现确定了NTRK2异构体失衡是内皮功能障碍的关键驱动因素，并支持异构体特异性RNA治疗作为血管再生和修复的有希望的策略。

研究人员表示，支气管肺发育不良（BPD）是一种慢性早产儿肺部疾病，没有治愈的治疗方法，其特征是肺泡生成和毛细血管形成受损。然而，内皮功能障碍的分子机制（BPD发病的关键驱动因素）仍然知之甚少。

附：英文原文

Title: Rebalancing NTRK2 isoforms promotes vascular regeneration in bronchopulmonary dysplasia

Author: Yunpei Zhang, Cheng Tan, Ziyi Liu, Xiangdi Mao, Cheng Jiang, Afzaal Nadeem Mohammed, Xiaolei Li, Renzhong Lu, Anmin Wang, Wusiman Maihemuti, Nicole Pek, Hailu Fu, Omar Milbes, Kavya Pandrangi, Colin Patrick Johnson, Varun Sekar, Yaping Liu, Li Lai, Gloria S. Pryhuber, Vladimir V. Kalinichenko, Yifei Miao, Minzhe Guo, Mingxia Gu

Issue&Volume: 2025-12-24

Abstract: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity with no curative therapy, characterized by impaired alveologenesis and capillary formation. However, the molecular mechanisms underlying endothelial dysfunction, a key driver of BPD pathogenesis, remain poorly understood. Through multiomic profiling of endothelial cells isolated from human BPD lungs, we identified an expansion of general capillary endothelial cells (gCaps) marked by neurotrophic receptor tyrosine kinase 2 (NTRK2). Notably, we uncovered a critical isoform switch that governs gCap regeneration. Full-length NTRK2 (NTRK2-FL) promoted gCap repair after hyperoxic injury, whereas RBFOX2-mediated splicing of NTRK2-FL into a truncated isoform (NTRK2-T1) contributed to maladaptive responses and persistent alveolar simplification. Restoring NTRK2-FL using lipid nanoparticle-delivered mRNA promoted angiogenesis in vessel organoids and reversed alveolar simplification in hyperoxic mice. These findings identified NTRK2 isoform imbalance as a key driver of endothelial dysfunction and support isoform-specific RNA therapy as a promising strategy for vascular regeneration and repair.

DOI: 10.1016/j.stem.2025.12.006

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00440-0