Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth.
Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth.
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DOI：
10.1161/circulationaha.114.009124
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发表时间：
2014-05-27
期刊：
影响因子：
37.8
通讯作者：
Thébaud B
中科院分区：
文献类型：
--
作者：
Alphonse RS;Vadivel A;Fung M;Shelley WC;Critser PJ;Ionescu L;O'Reilly M;Ohls RK;McConaghy S;Eaton F;Zhong S;Yoder M;Thébaud B
支气管肺发育不良和肺气肿是由肺泡发育受损或肺泡破坏引起的危及生命的疾病。这两种疾病都缺乏有效的治疗方法。血管生成生长因子促进肺泡的生长，有助于肺泡的维持。内皮细胞集落形成细胞(ECFC)是循环内皮细胞的一个亚群，具有自我更新和新生血管形成的能力。我们假设，在发育中的肺中存在常驻ECFC，在实验性支气管肺发育不良的肺泡生长受阻期间，它们受到损害，外源性ECFCs恢复被破坏的肺泡生长。人胎肺和新生大鼠肺中含有ECFCs，当移植到免疫缺陷小鼠体内时，ECFCs具有强大的增殖能力、二次克隆形成和体内新生血管形成。相反，体外高氧暴露的人胎肺内皮细胞和新生大鼠高氧肺泡生长停滞大鼠肺内皮细胞增殖较少，克隆形成能力降低，形成的毛细血管样网络较少。经颈静脉注射人脐血来源的ECFCs后，肺泡发育受阻，恢复了肺功能，肺泡和肺血管生长，并减轻了肺动脉高压。肺ECFC集落和毛细血管样网络形成能力也得到恢复。低ECFC植入率和无细胞ECFC来源的条件培养液的保护作用表明存在旁分泌效应。ECFC治疗的长期(10个月)评估显示，肺结构、运动能力和肺动脉高压持续改善，没有不良反应。ECFC功能受损可能导致肺泡生长受阻。脐带血来源的ECFC疗法可能为以肺泡损伤为特征的肺部疾病提供新的治疗选择。
Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth–arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood–derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. Impaired ECFC function may contribute to arrested alveolar growth. Cord blood–derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.