Genetically engineered distal airway stem cell transplantation protects mice from pulmonary infection
Genetically engineered distal airway stem cell transplantation protects mice from pulmonary infection
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基因工程远端气道干细胞移植可保护小鼠免受肺部感染
DOI：
10.15252/emmm.201810233
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Jin-fu Xu
中科院分区：
文献类型：
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作者：
Yue-qing Zhou;Yun Shi;Ling Yang;Yu-fen Sun;Yu-fei Han;Zi-xian Zhao;Yu-jia Wang;Ying Liu;Ying Liu;Ting Zhang;Tao Ren;Tina P Dale;Nicholas R Forsyth;Fa-guang Jin;Jie-ming Qu;Wei Zuo;Jin-fu Xu
严重的肺部感染是对人类健康的主要威胁，伴随着高昂的医疗费用、长时间的住院要求和高死亡率。迫切需要新的抗菌素治疗策略来解决抗生素耐药性和持续性细菌感染的出现。在这项研究中，我们证明了一种天然抗菌肽LL-37在转基因小鼠中的结构性表达有助于清除铜绿假单胞菌(PAO1)，这是临床肺部感染的主要病原体。将表达IL-37基因的成年小鼠远端呼吸道干细胞(DASCs)原位移植到损伤的小鼠肺灶内，可使细胞大规模整合并长期释放宿主防御肽，保护小鼠免受细菌性肺炎和低氧血症的影响。此外，分离、扩增和基因工程了成人DASCs的相关基因，以证明成功构建了抗感染的人工肺。总之，我们基于干细胞的基因传递治疗平台为应对反复肺部感染提出了一种新的战略，并提供了未来的翻译机会。
Severe pulmonary infection is a major threat to human health accompanied by substantial medical costs, prolonged inpatient requirements, and high mortality rates. New antimicrobial therapeutic strategies are urgently required to address the emergence of antibiotic resistance and persistent bacterial infections. In this study, we show that the constitutive expression of a native antimicrobial peptide LL‐37 in transgenic mice aids in clearing Pseudomonas aeruginosa (PAO1), a major pathogen of clinical pulmonary infection. Orthotopic transplantation of adult mouse distal airway stem cells (DASCs), genetically engineered to express LL‐37, into injured mouse lung foci enabled large‐scale incorporation of cells and long‐term release of the host defense peptide, protecting the mice from bacterial pneumonia and hypoxemia. Further, correlates of DASCs in adult humans were isolated, expanded, and genetically engineered to demonstrate successful construction of an anti‐infective artificial lung. Together, our stem cell‐based gene delivery therapeutic platform proposes a new strategy for addressing recurrent pulmonary infections with future translational opportunities.