利用双同源重组谱系示踪技术揭示肺损后肺泡干细胞再生起源

Dual Recombinases-Mediated Genetic Tracing Reveals the Cellular Origin of Alveolar Stem Cells after Lung Injury

肺脏修复再生是肺领域研究热点。在一些肺脏疾病中肺泡上皮结构受损,需要肺泡上皮干细胞的参与才能完成修复。因此揭示肺泡上皮干细胞的再生起源对肺脏疾病的防治具有重要临床意义。领域内既往研究一致认为肺泡II型上皮细胞(AT2细胞)属于肺泡上皮干细胞,不仅可以自我增殖还可以分化为AT1细胞。近年来有研究认为AT2还可以来源于支气管棒状细胞(club细胞)以及AT1细胞。然而这些研究中用来标记club细胞和AT1细胞的传统谱系示踪工具存在非特异性标记问题,导致这些结论存在重大科学争议。为阐明科学争议,该团队通过构建一系列更为精准的双同源重组谱系示踪新技术实现了对肺上皮细胞类型的特异性遗传靶向,并结合多种肺脏损伤模型揭示了新生AT2细胞除来源于AT2细胞自我增殖外,还可来源于club细胞、支气管肺泡干细胞(BASCs),而不会来源于AT1细胞,并阐明Notch信号通路参与调控club细胞和BASCs向AT2细胞命运转分化。阐明AT2细胞再生起源为肺部疾病研究提供重要研究基础,新开发的双同源重组谱系示踪技术可被广泛应用于发育生物学、遗传学和再生医学相关研究。

Lung repair and regeneration have emerged as a pivotal area of research in pulmonology.In some lung diseases,the alveolar epithelial structure is damaged and requires the involvement of alveolar stem cells to regenerate the damaged areas.Consequently,elucidating the origins of alveolar stem cells holds immense clinical importance for the prevention and treatment of lung diseases.Previous studies have consistently identified AT2cells(alveolar epithelial type II cells)as alveolar stem cells,capable of self-renewal and differentiation into AT1cells.Nevertheless,recent investigations have proposed an alternative hypothesis,suggesting that AT2 cells can also originate from bronchiolar club cells and alveolar AT1 cells.However,the conventional lineage tracing techniques employed in these studies have been plagued with non-specific labeling issues,resulting in inconclusive findings.To address this controversy,this team has developed a suite of more precise dual recombinases-mediated genetic tools for the specific labeling of lung epithelial cell types.By integrating these tools with multiple lung injury models,this article has uncovered that new AT2 cells can originate from club cells and BASCs(bronchoalveolar stem cells),in addition to the self-renewal of AT2 cells,but not from AT1 cells.Furthermore,the study has revealed that the Notch signaling pathway plays a crucial role in regulating the transition of club cells and BASCs into AT2 cells.Elucidating the origins of AT2 cells during lung repair provides novel insights for the treatment of lung diseases.The dual recombination lineage tracing technique established in this article holds vast potential for broader applications in the fields of developmental biology,genetics,and regenerative medicine.