The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3800, Australia.
Clin Sci (Lond). 2020 Oct 30;134(20):2665-2679. doi: 10.1042/CS20200859.
There is a growing appreciation of the role of lung stem/progenitor cells in the development and perpetuation of chronic lung disease including idiopathic pulmonary fibrosis. Human amniotic epithelial cells (hAECs) were previously shown to improve lung architecture in bleomycin-induced lung injury, with the further suggestion that hAECs obtained from term pregnancies possessed superior anti-fibrotic properties compared with their preterm counterparts. In the present study, we aimed to elucidate the differential effects of hAECs from term and preterm pregnancies on lung stem/progenitor cells involved in the repair. Here we showed that term hAECs were better able to activate bronchioalveolar stem cells (BASCs) and type 2 alveolar epithelial cells (AT2s) compared with preterm hAECs following bleomycin challenge. Further, we observed that term hAECs restored TGIF1 and TGFβ2 expression levels, while increasing c-MYC expression despite an absence of significant changes to Wnt/β-catenin signaling. In vitro, term hAECs increased the average size and numbers of BASC and AT2 colonies. The gene expression levels of Wnt ligands were higher in term hAECs, and the expression levels of BMP4, CCND1 and CDC42 were only increased in the BASC and AT2 organoids co-cultured with hAECs from term pregnancies but not preterm pregnancies. In conclusion, term hAECs were more efficient at activating the BASC niche compared with preterm hAECs. The impact of gestational age and/or complications leading to preterm delivery should be considered when applying hAECs and other gestational tissue-derived stem and stem-like cells therapeutically.
人们越来越认识到肺干/祖细胞在慢性肺疾病（包括特发性肺纤维化）的发展和持续中的作用。先前已经表明，人羊膜上皮细胞（hAECs）可改善博莱霉素诱导的肺损伤中的肺结构，并且进一步表明，与早产 hAECs 相比，来自足月妊娠的 hAECs 具有更好的抗纤维化特性。在本研究中，我们旨在阐明足月和早产妊娠的 hAECs 对参与修复的肺干/祖细胞的差异影响。在这里，我们显示与早产 hAECs 相比，足月 hAECs 在博莱霉素挑战后更能激活支气管肺泡干细胞（BASCs）和 2 型肺泡上皮细胞（AT2s）。此外，我们观察到尽管 Wnt/β-catenin 信号没有明显变化，但足月 hAECs 恢复了 TGIF1 和 TGFβ2 的表达水平，同时增加了 c-MYC 的表达。在体外，足月 hAECs 增加了 BASC 和 AT2 集落的平均大小和数量。足月 hAECs 中的 Wnt 配体基因表达水平较高，而仅在与足月妊娠来源的 hAECs 共培养的 BASC 和 AT2 类器官中，BMP4、CCND1 和 CDC42 的表达水平增加，而在早产妊娠来源的 hAECs 共培养的 BASC 和 AT2 类器官中则没有增加。总之，与早产 hAECs 相比，足月 hAECs 更有效地激活 BASC 生态位。在应用 hAECs 和其他来自妊娠组织的干细胞和类干细胞治疗时，应考虑胎龄和/或导致早产的并发症的影响。
