Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States.
Division of Neonatology and Pulmonary Biology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, United States.
Am J Physiol Lung Cell Mol Physiol. 2024 Jul 1;327(1):L114-L125. doi: 10.1152/ajplung.00274.2023. Epub 2024 May 21.
Bronchopulmonary dysplasia (BPD) is a severe complication of preterm births, which develops due to exposure to supplemental oxygen and mechanical ventilation. Published studies demonstrated that the number of endothelial progenitor cells (EPC) is decreased in mouse and human BPD lungs and that adoptive transfer of EPC is an effective approach in reversing the hyperoxia-induced lung damage in mouse model of BPD. Recent advancements in macrophage biology identified the specific subtypes of circulating and resident macrophages mediating the developmental and regenerative functions in the lungs. Several studies reported the successful application of macrophage therapy in accelerating the regenerative capacity of damaged tissues and enhancing the therapeutic efficacy of other transplantable progenitor cells. In the present study, we explored the efficacy of combined cell therapy with EPC and resident alveolar macrophages (rAM) in hyperoxia-induced BPD mouse model. rAM and EPC were purified from neonatal mouse lungs and were used for adoptive transfer to the recipient neonatal mice exposed to hyperoxia. Adoptive transfer of rAM alone did not result in engraftment of donor rAM into the lung tissue but increased the mRNA level and protein concentration of proangiogenic CXCL12 chemokine in recipient mouse lungs. Depletion of rAM by chlodronate-liposomes decreased the retention of donor EPC after their transplantation into hyperoxia-injured lungs. Adoptive transfer of rAM in combination with EPC enhanced the therapeutic efficacy of EPC as evidenced by increased retention of EPC, increased capillary density, improved arterial oxygenation, and alveolarization in hyperoxia-injured lungs. Dual therapy with EPC and rAM has promise in human BPD. Recent studies demonstrated that transplantation of lung-resident endothelial progenitor cells (EPC) is an effective therapy in mouse model of bronchopulmonary dysplasia (BPD). However, key factors regulating the efficacy of EPC are unknown. Herein, we demonstrate that transplantation of tissue-resident alveolar macrophages (rAM) increases CXCL12 expression in neonatal mouse lungs. rAM are required for retention of donor EPC in hyperoxia-injured lungs. Co-transplantation of rAM and EPC improves the efficacy of EPC therapy in mouse BPD model.
支气管肺发育不良（BPD）是早产儿的严重并发症，由于暴露于补充氧气和机械通气而发展。已发表的研究表明，在患有 BPD 的小鼠和人类肺部中内皮祖细胞（EPC）的数量减少，并且 EPC 的过继转移是逆转 BPD 小鼠模型中高氧诱导的肺损伤的有效方法。巨噬细胞生物学的最新进展确定了循环和驻留巨噬细胞的特定亚型，介导了肺部的发育和再生功能。一些研究报告了巨噬细胞疗法在加速受损组织的再生能力和增强其他可移植祖细胞的治疗效果方面的成功应用。在本研究中，我们探索了 EPC 和驻留肺泡巨噬细胞（rAM）联合细胞治疗在高氧诱导的 BPD 小鼠模型中的疗效。rAM 和 EPC 从新生小鼠肺中纯化，并用于过继转移到暴露于高氧的受体新生小鼠中。单独过继转移 rAM 不会导致供体 rAM 植入肺组织，但会增加受体小鼠肺中促血管生成 CXCL12 趋化因子的 mRNA 水平和蛋白浓度。氯膦酸盐脂质体耗竭 rAM 会降低供体 EPC 在移植到高氧损伤的肺后保留。rAM 与 EPC 的过继转移增强了 EPC 的治疗效果，表现为 EPC 的保留增加、毛细血管密度增加、高氧损伤肺的动脉氧合和肺泡化改善。EPC 和 rAM 的双重治疗有望用于人类 BPD。最近的研究表明，肺驻留内皮祖细胞（EPC）的移植是支气管肺发育不良（BPD）小鼠模型的有效治疗方法。然而，调节 EPC 疗效的关键因素尚不清楚。在此，我们证明移植组织驻留的肺泡巨噬细胞（rAM）可增加新生小鼠肺中 CXCL12 的表达。rAM 是高氧损伤肺中供体 EPC 保留所必需的。rAM 和 EPC 的共移植可改善 BPD 小鼠模型中 EPC 治疗的疗效。
