Lithopoulos Marissa A, Strueby Lannae, O'Reilly Megan, Zhong Shumei, Möbius Marius A, Eaton Farah, Fung Moses, Hurskainen Maria, Cyr-Depauw Chanèle, Suen Colin, Xu Liqun, Collins Jennifer J P, Vadivel Arul, Stewart Duncan J, Burger Dylan, Thébaud Bernard
Regenerative Medicine Program and.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Am J Respir Crit Care Med. 2022 May 15;205(10):1186-1201. doi: 10.1164/rccm.202012-4520OC.
Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, differentiation ability, and transcriptional profiles. The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased neurosphere formation and altered neural progenitor cell transcriptional signatures. Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.
支气管肺发育不良是一种源于早产的慢性呼吸系统疾病，与神经发育异常有关。目前，对于支气管肺发育不良及其相关脑损伤尚无有效的治疗方法。在临床前试验中，间充质基质细胞疗法有望成为支气管肺发育不良的一种治疗选择。为了研究多因素新生儿小鼠肺损伤模型是否会扰乱神经祖细胞功能，并评估人脐带间充质基质细胞外泌体减轻肺部和神经损伤的能力。在出生后第7天或第8天的小鼠腹腔内注射脂多糖，并在出生后第9天或第10天用40%氧气通气8小时。治疗组动物在通气前经气管内给予脐带间充质基质细胞来源的外泌体。对肺形态、血管生成和炎症进行量化分析。从脑室下区和海马体中分离神经祖细胞，并评估其自我更新、分化能力和转录谱。多因素肺损伤模型产生了类似支气管肺发育不良的肺泡和血管稀疏。肺损伤小鼠的神经祖细胞显示神经球和少突胶质细胞形成减少，以及炎症转录特征。用间充质基质细胞外泌体治疗的小鼠在肺结构、血管生成和炎症调节方面有显著改善。此外，我们观察到神经球形成显著增加，神经祖细胞转录特征发生改变。我们的多因素肺损伤模型损害了神经祖细胞功能。经气管内给予间充质基质细胞来源的外泌体可减轻观察到的肺部和神经改变。
