Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT+ Endothelial Progenitor Cells.
Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT+ Endothelial Progenitor Cells.
复制标题
出生后肺泡发生依赖于 c-KIT 内皮祖细胞中的 FOXF1 信号传导。
DOI：
10.1164/rccm.201812-2312oc
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发表时间：
2019
影响因子：
24.7
通讯作者：
Kalinichenko,VladimirV
中科院分区：
文献类型：
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作者：
Ren,Xiaomeng;Ustiyan,Vladimir;Guo,Minzhe;Wang,Guolun;Bolte,Craig;Zhang,Yufang;Xu,Yan;Whitsett,JeffreyA;Kalin,TanyaV;Kalinichenko,VladimirV
理论基础：肺泡形成中断与严重的儿科肺部疾病有关，包括支气管肺发育不良(BPD)。虽然c-kit+内皮细胞(EC)前体细胞在胚胎和新生儿肺组织中含量丰富，但它们在肺泡间隔中的作用以及这些细胞的治疗潜力尚不清楚。目的：确定c-kit+EC前体细胞是否刺激新生儿肺组织的肺泡生成。方法：应用新生儿人和小鼠肺组织的单细胞RNA测序、免疫染色和FACS分析，鉴定人和小鼠肺c-kit+EC前体细胞共有的转录和信号网络。利用围产期高氧性肺损伤小鼠模型，研究了c-kit+EC前体细胞在新生大鼠肺内存活、增殖和植入的分子机制。测量和主要结果：表达PECAM-1、CD34、VE-Cherin、Flk1和TIE2的肺c-kit+EC前体细胞缺乏成熟的动脉、静脉和淋巴细胞表面标志物。C-kit+ECs的转录信号在小鼠和人肺中保守，并富含FOXF1调节的转录靶点。BPD患儿肺组织中FOXF1和c-kit的表达减少。在小鼠中，新生儿高氧减少了c-kit+EC祖细胞的数量。Foxf1单倍体缺失或内皮细胞特异性缺失可增加c-kit+ECs的凋亡率，降低其增殖能力。Foxf1orc-Kit的失活引起肺泡的简化。将c-kit+ECs过继转移到新生小鼠的循环中，增加了新生小鼠的肺血管生成，防止了高氧暴露下的肺泡简化。结论：c-kit+EC前体细胞治疗BPD是一种有益的治疗方法。
Rationale:Disruption of alveologenesis is associated with severe pediatric lung disorders, including bronchopulmonary dysplasia (BPD). Although c-KIT+endothelial cell (EC) progenitors are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown.Objectives:To determine whether c-KIT+EC progenitors stimulate alveologenesis in the neonatal lung.Methods:We used single-cell RNA sequencing of neonatal human and mouse lung tissues, immunostaining, and FACS analysis to identify transcriptional and signaling networks shared by human and mouse pulmonary c-KIT+EC progenitors. A mouse model of perinatal hyperoxia-induced lung injury was used to identify molecular mechanisms that are critical for the survival, proliferation, and engraftment of c-KIT+EC progenitors in the neonatal lung.Measurements and Main Results:Pulmonary c-KIT+EC progenitors expressing PECAM-1, CD34, VE-Cadherin, FLK1, and TIE2 lacked mature arterial, venal, and lymphatic cell-surface markers. The transcriptomic signature of c-KIT+ECs was conserved in mouse and human lungs and enriched in FOXF1-regulated transcriptional targets. Expression of FOXF1 and c-KIT was decreased in the lungs of infants with BPD. In the mouse, neonatal hyperoxia decreased the number of c-KIT+EC progenitors. Haploinsufficiency or endothelial-specific deletion ofFoxf1in mice increased apoptosis and decreased proliferation of c-KIT+ECs. Inactivation of eitherFoxf1orc-Kitcaused alveolar simplification. Adoptive transfer of c-KIT+ECs into the neonatal circulation increased lung angiogenesis and prevented alveolar simplification in neonatal mice exposed to hyperoxia.Conclusions:Cell therapy involving c-KIT+EC progenitors can be beneficial for the treatment of BPD.