Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
Department of Physiology, University of Alberta, Edmonton, Canada.
Cytotherapy. 2018 Jan;20(1):108-125. doi: 10.1016/j.jcyt.2017.09.003. Epub 2017 Oct 20.
Bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disrupted lung growth, is the most common complication in extreme premature infants. BPD leads to persistent pulmonary disease later in life. Alveolar epithelial type 2 cells (AEC2s), a subset of which represent distal lung progenitor cells (LPCs), promote normal lung growth and repair. AEC2 depletion may contribute to persistent lung injury in BPD. We hypothesized that induced pluripotent stem cell (iPSC)-derived AECs prevent lung damage in experimental oxygen-induced BPD.
Mouse AECs (mAECs), miPSCs/mouse embryonic stem sells, human umbilical cord mesenchymal stromal cells (hUCMSCs), human (h)iPSCs, hiPSC-derived LPCs and hiPSC-derived AECs were delivered intratracheally to hyperoxia-exposed newborn mice. Cells were pre-labeled with a red fluorescent dye for in vivo tracking.
Airway delivery of primary mAECs and undifferentiated murine pluripotent cells prevented hyperoxia-induced impairment in lung function and alveolar growth in neonatal mice. Similar to hUCMSC therapy, undifferentiated hiPSCs also preserved lung function and alveolar growth in hyperoxia-exposed neonatal NOD/SCID mice. Long-term assessment of hiPSC administration revealed local teratoma formation and cellular infiltration in various organs. To develop a clinically relevant cell therapy, we used a highly efficient method to differentiate hiPSCs into a homogenous population of AEC2s. Airway delivery of hiPSC-derived AEC2s and hiPSC-derived LPCs, improved lung function and structure and resulted in long-term engraftment without evidence of tumor formation.
hiPSC-derived AEC2 therapy appears effective and safe in this model and warrants further exploration as a therapeutic option for BPD and other lung diseases characterized by AEC injury.
支气管肺发育不良（BPD）是一种以肺生长障碍为特征的慢性肺部疾病，是极早产儿最常见的并发症。BPD 会导致婴儿后期持续性肺部疾病。肺泡上皮 2 型细胞（AEC2），其中一部分代表远端肺祖细胞（LPC），促进正常肺生长和修复。AEC2 耗竭可能导致 BPD 中持续性肺损伤。我们假设诱导多能干细胞（iPSC）衍生的 AEC 可预防实验性氧诱导 BPD 中的肺损伤。
将小鼠 AEC（mAEC）、miPSC/小鼠胚胎干细胞、人脐带间充质基质细胞（hUCMSC）、人（h）iPSC、hiPSC 衍生的 LPC 和 hiPSC 衍生的 AEC 通过气管内途径递送至新生小鼠的高氧暴露环境中。细胞预先用红色荧光染料标记以进行体内追踪。
气道输送原代 mAEC 和未分化的鼠多能细胞可预防新生小鼠高氧诱导的肺功能障碍和肺泡生长受损。与 hUCMSC 治疗类似，未分化的 hiPSC 也可维持高氧暴露的新生 NOD/SCID 小鼠的肺功能和肺泡生长。hiPSC 给药的长期评估显示在各种器官中有局部畸胎瘤形成和细胞浸润。为了开发一种临床相关的细胞治疗方法，我们使用一种高效的方法将 hiPSC 分化为同质的 AEC2 群体。气道输送 hiPSC 衍生的 AEC2 和 hiPSC 衍生的 LPC 可改善肺功能和结构，并实现长期植入而无肿瘤形成的证据。
在该模型中，hiPSC 衍生的 AEC2 治疗似乎有效且安全，值得进一步探索作为以 AEC 损伤为特征的 BPD 和其他肺部疾病的治疗选择。
