Bone Marrow Stromal Cells Attenuate Lung Injury in a Murine Model of Neonatal Chronic Lung Disease
Bone Marrow Stromal Cells Attenuate Lung Injury in a Murine Model of Neonatal Chronic Lung Disease
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DOI：
10.1164/rccm.200902-0242oc
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发表时间：
2009-12-01
影响因子：
24.7
通讯作者：
Kourembanas, Stella
中科院分区：
文献类型：
--
作者：
Aslam, Muhammad;Baveja, Rajiv;Kourembanas, Stella
理由：新生儿慢性肺病，即支气管肺发育不良（BPD），尽管在极低出生体重婴儿的治疗方面取得了进展，但仍是早产的严重并发症。鉴于骨髓基质细胞（BMSCs；间充质干细胞）在肺和心血管损伤模型中的保护作用，我们在小鼠BPD模型中测试了它们的治疗潜力。方法：暴露于高氧环境（75% O-2）的新生小鼠在第4天静脉注射骨髓间充质干细胞或骨髓间充质干细胞条件培养基（CM），并在第14天评估肺形态测量、与肺动脉高压相关的血管变化和肺细胞因子谱。测量结果和主要结果：注射骨髓间充质干细胞而不注射肺动脉平滑肌细胞（PASMCs）可减少肺泡损失和肺部炎症，并预防肺动脉高压。尽管在高氧肺中移植的供体骨髓间充质干细胞比在正常氧对照中多，但总体上较少的数量表明除了直接的组织修复外，还存在保护机制。骨髓间充质干细胞- cm比骨髓间充质干细胞具有更明显的预防血管重构和肺泡损伤的作用。与pasmc - cm处理的对照组相比，处理动物在高氧第14天肺泡数量正常，肺中性粒细胞和巨噬细胞积累急剧减少。巨噬细胞刺激因子I和骨桥蛋白在骨髓间充质干细胞- cm中均呈高水平，可能参与了这种免疫调节。结论：骨髓间充质干细胞在体内通过释放免疫调节因子，以旁分泌方式改善BPD的实质和血管损伤。我们的研究表明，骨髓间充质干细胞及其分泌的因子为目前缺乏有效治疗的肺部疾病提供了新的治疗方法。
Rationale: Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants.Objectives: Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD.Methods: Neonatal mice exposed to hyperoxia (75% O-2) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile.Measurements and Main Results: Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC-CM-treated controls. Macrophage stimulating factor I and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation.Conclusions: BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.