Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland.
Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland.
Int J Mol Sci. 2021 Nov 27;22(23):12842. doi: 10.3390/ijms222312842.
Ventilator-induced lung injury (VILI) frequently worsens acute respiratory distress syndrome (ARDS) severity. Human mesenchymal stem/stromal cells (MSCs) offer considerable therapeutic promise, but the key impediments of clinical translation stem from limitations due to cell source and availability, and concerns regarding the loss of efficacy following cryopreservation. These experiments compared the efficacy of umbilical-cord-derived MSCs (UC-MSCs), a readily available and homogenous tissue source, to the previously more widely utilised bone-marrow-derived MSCs (BM-MSCs). We assessed their capacity to limit inflammation, resolve injury and enhance repair in relevant lung mechanical stretch models, and the impact of cryopreservation on therapeutic efficacy.
In , confluent alveolar epithelial layers were subjected to cyclic mechanical stretch (22% equibiaxial strain) and wound injury, and the potential of the secretome from BM- and UC-derived MSCs to attenuate epithelial inflammation and cell death, and enhance wound repair was determined. In , anesthetized rats underwent VILI, and later received, in a randomised manner, 1 × 10 MSCs/kg intravenously, that were: (i) fresh BM-MSCs, (ii) fresh UC-MSCs or (iii) cryopreserved UC-MSCs. Control animals received a vehicle (PBS). The extent of the resolution of inflammation and injury, and repair was measured at 24 h.
Conditioned medium from BM-MSCs and UC-MSCs comparably decreased stretch-induced pulmonary epithelial inflammation and cell death. BM-MSCs and UC-MSCs comparably enhanced wound resolution. In animals subjected to VILI, both fresh BM-MSCs and UC-MSCs enhanced injury resolution and repair, while cryopreserved UC-MSCs comparably retained their efficacy.
Cryopreserved UC-MSCs can reduce stretch-induced inflammation and cell death, enhance wound resolution, and enhance injury resolution and repair following VILI. Cryopreserved UC-MSCs represent a more abundant, cost-efficient, less variable and equally efficacious source of therapeutic MSC product.
呼吸机引起的肺损伤（VILI）经常使急性呼吸窘迫综合征（ARDS）的严重程度恶化。人骨髓间充质干细胞（MSCs）具有很大的治疗潜力，但临床转化的关键障碍源于细胞来源和可用性的限制，以及对冷冻保存后效力丧失的担忧。这些实验比较了脐带来源的 MSCs（UC-MSCs），一种现成的同质组织来源，与以前更广泛使用的骨髓来源的 MSCs（BM-MSCs）的疗效。我们评估了它们在相关肺机械拉伸模型中限制炎症、解决损伤和增强修复的能力，以及冷冻保存对治疗效果的影响。
在体外，在培养的肺泡上皮层上施加周期性机械拉伸（22%的等张应变）和伤口损伤，并确定 BM 和 UC 来源的 MSC 的分泌产物在减轻上皮炎症和细胞死亡以及增强伤口修复方面的潜力。在体内，麻醉大鼠经历 VILI，然后随机静脉内给予 1×10 MSC/kg 的 MSC，分别为：（i）新鲜 BM-MSCs，（ii）新鲜 UC-MSCs 或（iii）冷冻保存的 UC-MSCs。对照动物接受载体（PBS）。在 24 小时时测量炎症和损伤的缓解程度以及修复程度。
BM-MSCs 和 UC-MSCs 的条件培养基均可降低拉伸诱导的肺上皮炎症和细胞死亡。BM-MSCs 和 UC-MSCs 均可增强伤口愈合。在经历 VILI 的动物中，新鲜的 BM-MSCs 和 UC-MSCs 均增强了损伤的缓解和修复，而冷冻保存的 UC-MSCs 则保留了其疗效。
冷冻保存的 UC-MSCs 可减少拉伸诱导的炎症和细胞死亡，增强伤口愈合，并增强 VILI 后的损伤缓解和修复。冷冻保存的 UC-MSCs 代表了更丰富、成本效益更高、变化更小且同样有效的治疗性 MSC 产品来源。
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