Optimization of Targeted Cell Replacement Therapy: A New Approach for Lung Disease
Optimization of Targeted Cell Replacement Therapy: A New Approach for Lung Disease
复制标题
DOI：
10.1038/mt.2010.142
复制
发表时间：
2010-10-01
影响因子：
12.4
通讯作者：
Waddell, Thomas K.
中科院分区：
文献类型：
--
作者：
Duchesneau, Pascal;Wong, Amy P.;Waddell, Thomas K.
细胞替代疗法是治疗肺部疾病（如囊性纤维化）的一种很有前途的方法，尽管移植率需要提高。我们之前的研究表明，与静脉注射相比，经气管给药可改善肺细胞潴留。在这里，我们优化了用培养7天的骨髓细胞（BMCs）传递细胞的其他参数。BMC在肺中的滞留是剂量依赖性的。在细胞递送前2天，萘处理对BMC保留的影响最大。萘处理的供体扩增了CCSP+群体，增加了受体的保留效率。重复的萘处理和重复的细胞递送都导致更大的滞留。第二次细胞剂量的贡献很小，这表明第二次BMC的递送促进了第一次细胞的增殖。布苏芬诱导的骨髓抑制使外源性BMC的保留增加了20倍。这些BMC有助于CCSP的重建。使用最佳递送技术和细胞角蛋白18驱动的绿色荧光蛋白（GFP）报告小鼠，我们检测到的GFP增加了三倍，表明BMC向上皮细胞分化了更多。我们提出，改进的肺移植将增加细胞替代，从而成为更有效的治疗各种肺部疾病的方法。
Cell replacement therapy is a promising approach for treatment of lung disease such as cystic fibrosis, although rates of engraftment need to be improved. We previously showed improved cell retention in the lung using transtracheal delivery compared to intravenous injection. Here, we optimized other parameters of cell delivery using 7-day cultured bone marrow cells (BMCs). Retention of BMC in the lung was dose-dependent. Naphthalene treatment had maximal effects on BMC retention when given 2 days before cell delivery. Naphthalene treatment of the donor amplified a CCSP+ population and increased retention efficiency in the recipient. Repeated naphthalene treatment and repeated cell delivery both resulted in greater retention. The contribution of the second cell dose was minimal suggesting that a second delivery of BMC promotes proliferation of the first. Busulfan-induced myelosuppression augmented retention of exogenous BMC by up to 20-fold. These BMC helped CCSP reconstitution. Using the optimal delivery techniques and cytokeratin-18-driven green fluorescent protein (GFP) reporter mice, we detected threefold more GFP suggesting more BMC differentiated to epithelial cells. We propose that improved engraftment in the lung will increase cell replacement and thus be a more efficient therapeutic approach for various lung diseases.