From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.). bthebaud@ohri.
Circulation. 2014 May 27;129(21):2144-57. doi: 10.1161/CIRCULATIONAHA.114.009124. Epub 2014 Apr 7.
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.
支气管肺发育不良和肺气肿是由肺泡发育不良或肺泡破坏引起的危及生命的疾病。这两种情况都缺乏有效的治疗方法。血管生成生长因子促进肺泡生长，并有助于肺泡维持。内皮祖细胞（ECFCs）是循环和常驻内皮细胞的一个子集，能够自我更新和形成新的血管。我们假设，在实验性支气管肺发育不良中，发育中的肺中存在常驻 ECFCs，它们在肺泡生长停滞期间受损，而外源性 ECFCs 可恢复受损的肺泡生长。
人胎肺和新生大鼠肺中含有 ECFCs，其具有强大的增殖潜力、在再接种时的次级集落形成以及在体内移植到免疫缺陷小鼠时形成新的血管。相比之下，体外暴露于高氧的人胎肺 ECFCs 和模拟支气管肺发育不良的高氧诱导的肺泡生长停滞的新生大鼠 ECFCs 增殖较少，克隆形成能力降低，形成的毛细血管样网络较少。在已建立的肺泡生长停滞后，经颈内静脉给予人脐带血来源的 ECFCs 可恢复肺功能、肺泡和肺血管生长，并减轻肺动脉高压。肺 ECFC 集落和毛细血管样网络形成能力也得到恢复。ECFC 低移植率和无细胞 ECFC 衍生条件培养基的保护作用提示存在旁分泌效应。ECFC 治疗的长期（10 个月）评估显示无不良反应，并持续改善肺结构、运动能力和肺动脉高压。
ECFC 功能受损可能导致肺泡生长停滞。脐带血来源的 ECFC 治疗可能为以肺泡损伤为特征的肺部疾病提供新的治疗选择。
