Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Department of Pharmaceutics, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA.
Reprod Toxicol. 2024 Oct;129:108673. doi: 10.1016/j.reprotox.2024.108673. Epub 2024 Jul 24.
Perinatal nicotine exposure via tobacco smoking results in increased proclivity to chronic lung disease (CLD); however, the underlying molecular mechanisms remain incompletely understood. We previously demonstrated that in addition to nicotine's direct effects on the developing lung, there are also adverse molecular alterations in bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to lung injury repair. Whether perinatal nicotine exposure via electronic-cigarette (e-cig) vaping also adversely affects BMSCs is unknown. This is highly relevant due to marked increase in e-cig vaping including by pregnant women. Hypothesizing that perinatal nicotine exposure via e-cig vaping predisposes BMSCs to a pro-myofibroblastic phenotype, pregnant rat dams were exposed to fresh air (control), vehicle (e-cig without nicotine), or e-cig (e-cig with nicotine) daily during pregnancy and lactation. At postnatal day 21, offspring BMSCs were isolated and studied for cell proliferation, migration, wound healing response, and expression of key Wnt and PPARγ signaling intermediates (β-catenin, LEF-1, PPARγ, ADRP and C/EBPα) and myogenic markers (fibronectin, αSMA, calponin) proteins using immunoblotting. Compared to controls, perinatal e-cig exposure resulted in significant decrease in BMSC proliferation, migration, and wound healing response. The expression of key Wnt signaling intermediates (β-catenin, LEF-1) and myogenic markers (fibronectin, αSMA, calponin) increased significantly, while PPARγ signaling intermediates (PPARγ, ADRP, and C/EBPα) decreased significantly. Based on these data, we conclude that perinatally e-cig exposed BMSCs demonstrate pro-myofibroblastic phenotype and impaired injury-repair potential, indicating a potentially similar susceptibility to CLD following perinatal nicotine exposure via vaping as seen following parenteral perinatal nicotine exposure.
通过吸烟使胎儿接触围产期尼古丁会导致慢性肺病（CLD）易感性增加；然而，其潜在的分子机制仍不完全清楚。我们之前的研究表明，除了尼古丁对发育中肺的直接作用外，骨髓间充质干细胞（BMSCs）也会发生不良的分子改变，而骨髓间充质干细胞对肺损伤修复至关重要。通过电子烟（e-cig）蒸气使胎儿接触围产期尼古丁是否也会对 BMSCs 产生不利影响尚不清楚。这一点非常重要，因为 e-cig 蒸气的使用显著增加，包括孕妇在内的人群都在使用。我们假设通过 e-cig 蒸气使胎儿接触围产期尼古丁会使 BMSCs 向肌成纤维表型转化，因此在妊娠和哺乳期期间，使孕鼠每天暴露于新鲜空气（对照组）、载体（不含尼古丁的 e-cig）或 e-cig（含尼古丁的 e-cig）中。在出生后第 21 天，分离出生后代的 BMSCs，通过免疫印迹法研究细胞增殖、迁移、伤口愈合反应以及关键 Wnt 和 PPARγ 信号转导中间物（β-catenin、LEF-1、PPARγ、ADRP 和 C/EBPα）和肌生成标志物（纤维连接蛋白、αSMA、钙调蛋白）的表达。与对照组相比，围产期 e-cig 暴露导致 BMSC 增殖、迁移和伤口愈合反应显著减少。关键 Wnt 信号转导中间物（β-catenin、LEF-1）和肌生成标志物（纤维连接蛋白、αSMA、钙调蛋白）的表达显著增加，而 PPARγ 信号转导中间物（PPARγ、ADRP 和 C/EBPα）的表达显著减少。基于这些数据，我们得出结论，围产期 e-cig 暴露的 BMSCs 表现出肌成纤维表型和受损的损伤修复潜能，这表明通过 e-cig 蒸气使胎儿接触围产期尼古丁与通过母体围产期尼古丁接触一样，可能使 BMSCs 对 CLD 具有相似的易感性。
