Endothelial progenitor cells derived from embryonic stem cells prevent alveolar simplification in a murine model of bronchopulmonary dysplasia.
Endothelial progenitor cells derived from embryonic stem cells prevent alveolar simplification in a murine model of bronchopulmonary dysplasia.
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DOI：
10.3389/fcell.2023.1209518
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发表时间：
2023
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
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简介：血管重塑和受损的肺泡发育是慢性肺部疾病如支气管肺发育不良（BPD）的标志。尽管新生儿保健取得了进展，但全球BPD病例的数量仍在继续增加。克服BPD中肺发育过早停滞的一种方法是通过内皮祖细胞（EPCs）的递送和植入刺激新生儿血管生成。一种这样的群体驻留在肺微血管系统中并表达FOXF 1和c-KIT。先前的研究表明，c-KIT+ FOXF 1 + EPCs对氧水平升高（高氧）高度敏感，并且在患有BPD的早产儿和高氧诱导的BPD小鼠模型中减少。我们假设，通过移植来自多能胚胎干细胞（ESC）的c-KIT+ FOXF 1 + EPCs恢复EPCs，将刺激高氧诱导的肺损伤小鼠的新生血管生成和肺泡形成。 方法：利用一种新的ESC细胞系与FOXF 1：GFP报告基因，我们在体外产生ESC衍生的c-KIT+ FOXF 1 + EPCs。使用含有FOXF 1：GFP和tdTomato转基因的第二个ESC系，我们将ESC分化为c-KIT+ FOXF 1 + EPCs，并在注射到高氧损伤小鼠的新生儿循环中后在体内追踪它们。在室内空气条件下恢复一段时间后，我们分析了c-KIT+ FOXF 1 + EPC移植，并定量了EPC移植后驻留和循环内皮细胞的数量、肺泡腔的大小和毛细血管密度。 结果与结论：在此，我们证明了将BMP 9添加到定向内皮分化方案中导致从多能ESC非常有效地产生c-KIT+ FOXF 1 + EPCs。ESC来源的c-KIT+ FOXF 1 + EPCs有效地植入高氧损伤小鼠的肺微血管，促进肺泡中的血管重塑，增加驻留和循环内皮细胞的数量，并改善肺泡化。总之，这些结果提供了一个原理证明，即用ESC衍生的c-KIT+ FOXF 1 + EPCs的细胞疗法可以防止高氧诱导的BPD小鼠模型中的肺泡简化。
Introduction: Vascular remodeling and compromised alveolar development are hallmarks of chronic pulmonary diseases such as bronchopulmonary dysplasia (BPD). Despite advances in neonatal healthcare the number of BPD cases worldwide continues to increase. One approach to overcoming the premature arrest in lung development seen in BPD is to stimulate neonatal angiogenesis via delivery and engraftment of endothelial progenitor cells (EPCs). One such population is resident to the pulmonary microvasculature and expresses both FOXF1 and c-KIT. Previous studies have shown that c-KIT+FOXF1+ EPCs are highly sensitive to elevated levels of oxygen (hyperoxia) and are decreased in premature infants with BPD and hyperoxia-induced BPD mouse models. We hypothesize that restoring EPCs through transplantation of c-KIT+FOXF1+ EPCs derived in vitro from pluripotent embryonic stem cells (ESCs), will stimulate neonatal angiogenesis and alveolarization in mice with hyperoxia-induced lung injury. Methods: Utilizing a novel ESC line with a FOXF1:GFP reporter, we generated ESC-derived c-KIT+FOXF1+ EPCs in vitro. Using a second ESC line which contains FOXF1:GFP and tdTomato transgenes, we differentiated ESCs towards c-KIT+FOXF1+ EPCs and tracked them in vivo after injection into the neonatal circulation of hyperoxia-injured mice. After a recovery period in room air conditions, we analyzed c-KIT+FOXF1+ EPC engraftment and quantified the number of resident and circulating endothelial cells, the size of alveolar spaces, and the capillary density after EPC transplantations. Results and conclusion: Herein, we demonstrate that addition of BMP9 to the directed endothelial differentiation protocol results in very efficient generation of c-KIT+FOXF1+ EPCs from pluripotent ESCs. ESC-derived c-KIT+FOXF1+ EPCs effectively engraft into the pulmonary microvasculature of hyperoxia-injured mice, promote vascular remodeling in alveoli, increase the number of resident and circulating endothelial cells, and improve alveolarization. Altogether, these results provide a proof-of-principle that cell therapy with ESC-derived c-KIT+FOXF1+ EPCs can prevent alveolar simplification in a hyperoxia-induced BPD mouse model.
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影响因子：
64.8
作者：
Gillich A;Zhang F;Farmer CG;Travaglini KJ;Tan SY;Gu M;Zhou B;Feinstein JA;Krasnow MA;Metzger RJ
通讯作者：
Metzger RJ
DOI：
10.3791/62391
发表时间：
2021-03-31
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Nelson EA;Qiu J;Chavkin NW;Hirschi KK
通讯作者：
Hirschi KK
影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
2.6
作者：
Dharmadhikari AV;Szafranski P;Kalinichenko VV;Stankiewicz P
通讯作者：
Stankiewicz P
影响因子：
1.2
作者：
Kalinichenko, VV;Gusarova, GA;Costa, RH
通讯作者：
Costa, RH