TGF-beta信号对肺干细胞的调控作用

In adult lung there are rare p63+/Krt5+ distal airway stem cells (DASC) residing in the basal layer of bronchioles, which are responsible for lung tissue repair and regeneration. The deficiency in stem cell number or function is the etiology of multiple lung diseases, such as pulmonary fibrosis, for which the parthenogenesis is usually irreversible. Here in this project, the applicants will use bleomycin-induced mouse lung injury model to study DASC behavior in the context of TGF-beta signaling, which is known as a highly activated pathway in lung fibrotic process. We will also address the molecular mechanism that how TGF-beta controls DASC behavior. Furthermore, we plan to expand DASC in vitro for intrapulmonary transplantation, and try to improve the stem cell transplantation efficiency by manipulating TGF-beta signal level. Altogether, our goal is to reveal the cellular/molecular mechanism of lung injury and repair, and meanwhile facilitate the application of stem cell transplantation in lung disease therapy. Our previous work on TGF-beta and lung stem cells (Zuo et.al.,Mol Cell, 2013; Zuo et.al., Nature, 2015) has established good foundation for current study.

在成人肺脏细支气管基底层位置存在着少量的p63+/Krt5+ 双阳性干细胞（称为DASC细胞），有介导损伤肺组织修复再生的功能。肺部干细胞数量的缺乏和功能的丧失往往是多种肺部疾病（如肺纤维化等）持续发展恶化的原因。 本课题以博莱霉素诱导的小鼠肺损伤为动物模型，研究在纤维化病变环境中高度激活的TGF-beta信号通路对DASC细胞生理活动的影响，并探讨其作用机制。在此基础之上，在体外培养扩增DASC细胞，研究如何通过操纵TGF-beta信号水平提高DASC的肺内移植效率。本研究有助于增进对肺脏损伤和修复机理的认识，同时为干细胞肺内移植的治疗实践提供了推动作用。本申请人在TGF-beta和肺干细胞领域的前期工作(Zuo et.al.,Mol Cell, 2013; Zuo et.al., Nature, 2015)为课题奠定了良好的基础。

支气管和肺泡的不可逆损伤可能导致多种难以治愈的肺部疾病。在各种针对这类疾病的潜在治疗手段中，寻找到具有再生能力的肺干细胞/前体细胞来重塑功能性肺组织是最具潜能的方案之一。在本文中，我们揭示了在气道上皮褶皱部位中微量存在的Krt5+ p63+肺干细胞（DASC）能够实现成体人肺脏再生。我们团队建立了利用支气管镜刷取微量组织并便捷地在体外分离培养人DASC的平台。经过大量扩增的人肺干细胞在移植到受损小鼠肺脏后，能够迅速再生出肺泡和支气管上皮层，同时再造受体的气-血交换系统，促进肺功能的恢复。而利用药物吡非尼酮抑制受损肺脏微环境内的TGF-β信号通路能够进一步提升移植的效率。