Activation of Human Mesenchymal Stem Cells Impacts Their Therapeutic Abilities in Lung Injury by Increasing Interleukin (IL)-10 and IL-1RN Levels
Activation of Human Mesenchymal Stem Cells Impacts Their Therapeutic Abilities in Lung Injury by Increasing Interleukin (IL)-10 and IL-1RN Levels
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DOI：
10.5966/sctm.2013-0033
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发表时间：
2013-11-01
影响因子：
6
通讯作者：
Rojas, Mauricio
中科院分区：
文献类型：
--
作者：
Bustos, Martha L.;Huleihel, Luai;Rojas, Mauricio
急性呼吸窘迫综合征（ARDS）是导致发病和死亡的重要原因，目前尚无有效的治疗方法。几项临床前研究表明，人间充质干细胞（hMSCs）具有免疫调节特性，对ARDS患者具有治疗潜力。hMSCs的临床应用有一些局限性，如从骨髓抽吸物中分离细胞所需的大量操作以及它们在动物模型和临床试验中抗炎作用的异质性。本研究的目的是通过评估在ARDS小鼠模型中使用前预活化hMSCs的后果来提高hMSCs的保护性抗炎能力。我们给内毒素血症小鼠注射了从椎体骨髓中分离的最低限度操作的hMSCs，有或没有预先用ARDS患者的血清激活。与从骨髓抽吸物获得的分离和体外扩增的hMSCs相比，最小操作的hMSCs在减少肺部炎症方面更有效。观察到最重要的作用是与活化的hMSCs，独立于其来源，这导致白细胞介素（IL）-10和IL-1受体拮抗剂（RN）的表达增加，这与通过减少肺损伤评分，肺水肿的发展，以及与非活化细胞相比支气管肺泡灌洗液炎性细胞和细胞因子的积累来增强其保护能力有关。该研究表明，在hMSC分离和扩增期间的低操作增加，以及在hMSC的治疗性使用之前的预活化，将确保hMSC的适当的免疫调节表型，降低其抗炎作用的异质性。
Acute respiratory distress syndrome (ARDS) is an important cause of morbidity and mortality, with no currently effective therapies. Several preclinical studies have shown that human mesenchymal stem cells (hMSCs) have therapeutic potential for patients with ARDS because of their immunomodulatory properties. The clinical use of hMSCs has some limitations, such as the extensive manipulation required to isolate the cells from bone marrow aspirates and the heterogeneity in their anti-inflammatory effect in animal models and clinical trials. The objective of this study was to improve the protective anti-inflammatory capacity of hMSCs by evaluating the consequences of preactivating hMSCs before use in a murine model of ARDS. We injected endotoxemic mice with minimally manipulated hMSCs isolated from the bone marrow of vertebral bodies with or without prior activation with serum from ARDS patients. Minimally manipulated hMSCs were more efficient at reducing lung inflammation compared with isolated and in vitro expanded hMSCs obtained from bone marrow aspirates. Where the most important effect was observed was with the activated hMSCs, independent of their source, which resulted in increased expression of interleukin (IL)-10 and IL-1 receptor antagonist (RN), which was associated with enhancement of their protective capacity by reduction of the lung injury score, development of pulmonary edema, and accumulation of bronchoalveolar lavage inflammatory cells and cytokines compared with nonactivated cells. This study demonstrates that a low manipulation during hMSC isolation and expansion increases, together with preactivation prior to the therapeutic use of hMSCs, would ensure an appropriate immunomodulatory phenotype of the hMSCs, reducing the heterogeneity in their anti-inflammatory effect.