Genetically engineered distal airway stem cell transplantation protects mice from pulmonary infection.,EMBO Molecular Medicine

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Genetically engineered distal airway stem cell transplantation protects mice from pulmonary infection.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-11-29 , DOI: 10.15252/emmm.201810233
Yue-Qing Zhou ₁ , Yun Shi _{2,

3} , Ling Yang ₁ , Yu-Fen Sun ₁ , Yu-Fei Han ₁ , Zi-Xian Zhao ₁ , Yu-Jia Wang ₁ , Ying Liu ₂ , Yu Ma _{2,

4} , Ting Zhang ₄ , Tao Ren ₂ , Tina P Dale ₅ , Nicholas R Forsyth ₅ , Fa-Guang Jin ₃ , Jie-Ming Qu _{6,

7} , Wei Zuo _{1,

2,

4,

8,

9} , Jin-Fu Xu ₁

Affiliation

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.

中文翻译：

基因工程远端气道干细胞移植可保护小鼠免受肺部感染。

严重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、长期的住院需求和高死亡率。迫切需要新的抗菌治疗策略来解决抗生素耐药性和持续细菌感染的出现。在这项研究中，我们发现转基因小鼠中天然抗菌肽 LL-37 的组成型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。将经过基因工程改造表达 LL-37 的成年小鼠远端气道干细胞 (DASC) 原位移植到受损的小鼠肺病灶中，可实现细胞的大规模掺入和宿主防御肽的长期释放，从而保护小鼠免受细菌性肺炎的侵害和低氧血症。此外，对成年人体内 DASC 的相关物进行了分离、扩增和基因改造，以证明抗感染人工肺的成功构建。总之，我们基于干细胞的基因传递治疗平台提出了一种新策略，通过未来的转化机会来解决复发性肺部感染。

更新日期：2020-01-09

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