Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity.
Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity.
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DOI：
10.1038/s41598-023-50717-w
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发表时间：
2024-01-23
影响因子：
4.6
通讯作者：
Cornfield, David N.
中科院分区：
文献类型：
--
作者：
Zanini, Fabio;Che, Xibing;Suresh, Nina E.;Knutsen, Carsten;Klavina, Paula;Xie, Yike;Domingo-Gonzalez, Racquel;Liu, Min;Kum, Alexander;Jones, Robert C.;Quake, Stephen R.;Alvira, Cristina M.;Cornfield, David N.
通过血管生成，肺微脉管系统快速扩张，驱动肺泡化，这是出生后发生的肺发育的最后阶段，并显着增加肺气体交换表面积。肺血管生成的破坏会导致长期的肺部结构和生理异常，包括支气管肺发育不良，这是一种以肺泡化受损为特征的疾病。尽管内皮细胞是肺血管生成的主要决定因素，但间充质细胞（MC）在血管生成和肺泡化中发挥着关键的双重作用。因此，我们对发育中的肺部进行了单细胞转录组学和原位成像，以分析肺泡化过程中和肺损伤背景下的间充质细胞。特定的间充质细胞亚型在出生时就存在，并且在肺泡化过程中多样性不断增加，甚至同时表达与更成熟的相关细胞不同的转录组谱。高氧抑制了 MC 的转录组进展，揭示了不同的细胞亚型脆弱性，周细胞和肌成纤维细胞受影响最大，改变了细胞间通讯，并导致 Acta1 表达细胞的出现。这些见解为新生儿肺部疾病的靶向治疗带来了希望，新生儿肺部疾病仍然是全世界婴儿发病和死亡的主要原因。
Rapid expansion of the pulmonary microvasculature through angiogenesis drives alveolarization, the final stage of lung development that occurs postnatally and dramatically increases lung gas-exchange surface area. Disruption of pulmonary angiogenesis induces long-term structural and physiologic lung abnormalities, including bronchopulmonary dysplasia, a disease characterized by compromised alveolarization. Although endothelial cells are primary determinants of pulmonary angiogenesis, mesenchymal cells (MC) play a critical and dual role in angiogenesis and alveolarization. Therefore, we performed single cell transcriptomics and in-situ imaging of the developing lung to profile mesenchymal cells during alveolarization and in the context of lung injury. Specific mesenchymal cell subtypes were present at birth with increasing diversity during alveolarization even while expressing a distinct transcriptomic profile from more mature correlates. Hyperoxia arrested the transcriptomic progression of the MC, revealed differential cell subtype vulnerability with pericytes and myofibroblasts most affected, altered cell to cell communication, and led to the emergence of Acta1 expressing cells. These insights hold the promise of targeted treatment for neonatal lung disease, which remains a major cause of infant morbidity and mortality across the world.
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