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Cytokine pre-activation of cryopreserved xenogeneic-free human mesenchymal stromal cells enhances resolution and repair following ventilator-induced lung injury potentially via a KGF-dependent mechanism
Intensive Care Medicine Experimental Pub Date : 2020-02-05 , DOI: 10.1186/s40635-020-0295-5 Shahd Horie 1, 2 , Sean Gaynard 2 , Mary Murphy 2, 3 , Frank Barry 2, 3 , Michael Scully 1, 2 , Daniel O'Toole 1, 2 , John G Laffey 1, 2, 4
Intensive Care Medicine Experimental Pub Date : 2020-02-05 , DOI: 10.1186/s40635-020-0295-5 Shahd Horie 1, 2 , Sean Gaynard 2 , Mary Murphy 2, 3 , Frank Barry 2, 3 , Michael Scully 1, 2 , Daniel O'Toole 1, 2 , John G Laffey 1, 2, 4
Affiliation
Background Human mesenchymal stem/stromal cells (hMSCs) represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome. Translational challenges include restoring hMSC efficacy following cryopreservation, developing effective xenogeneic-free (XF) hMSCs and establishing true therapeutic potential at a clinically relevant time point of administration. We wished to determine whether cytokine pre-activation of cryopreserved, bone marrow-derived XF-hMSCs would enhance their capacity to facilitate injury resolution following VILI and elucidate mechanisms of action. Methods Initially, in vitro studies examined the potential for the secretome from cytokine pre-activated XF-hMSCs to attenuate pulmonary epithelial injury induced by cyclic mechanical stretch. Later, anaesthetised rats underwent VILI and, 6 h following injury, were randomized to receive 1 × 10 7 XF-hMSC/kg that were (i) naive fresh, (ii) naive cryopreserved, (iii) cytokine pre-activated fresh or (iv) cytokine pre-activated cryopreserved, while control animals received (v) vehicle. The extent of injury resolution was measured at 24 h after injury. Finally, the role of keratinocyte growth factor (KGF) in mediating the effect of pre-activated XF-hMSCs was determined in a pulmonary epithelial wound repair model. Results Pre-activation enhanced the capacity of the XF-hMSC secretome to decrease stretch-induced pulmonary epithelial inflammation and injury. Both pre-activated fresh and cryopreserved XF-hMSCs enhanced resolution of injury following VILI, restoring oxygenation, improving lung compliance, reducing lung leak and improving resolution of lung structural injury. Finally, the secretome of pre-activated XF-hMSCs enhanced epithelial wound repair, in part via a KGF-dependent mechanism. Conclusions Cytokine pre-activation enhanced the capacity of cryopreserved, XF-hMSCs to promote injury resolution following VILI, potentially via a KGF-dependent mechanism.
中文翻译:
冷冻保存的无异种人间充质基质细胞的细胞因子预激活可能通过 KGF 依赖性机制增强呼吸机诱导的肺损伤后的分辨率和修复
背景人类间充质干/基质细胞 (hMSCs) 代表了呼吸机诱导的肺损伤 (VILI) 和急性呼吸窘迫综合征的一种有前景的治疗策略。转化挑战包括在冷冻保存后恢复 hMSC 的功效、开发有效的无异种 (XF) hMSC 以及在临床相关的给药时间点建立真正的治疗潜力。我们希望确定冷冻保存的骨髓来源的 XF-hMSC 的细胞因子预激活是否会增强其在 VILI 后促进损伤解决的能力并阐明作用机制。方法 最初,体外研究检查了细胞因子预激活的 XF-hMSC 的分泌组减轻由循环机械拉伸引起的肺上皮损伤的潜力。之后,麻醉的大鼠接受 VILI 治疗,并在受伤后 6 小时随机接受 1 × 10 7 XF-hMSC/kg,它们是 (i) 幼稚新鲜,(ii) 幼稚冷冻保存,(iii) 细胞因子预活化新鲜或 (iv)细胞因子预活化冷冻保存,而对照动物接受(v)载体。在损伤后 24 小时测量损伤消退的程度。最后,在肺上皮伤口修复模型中确定了角质形成细胞生长因子 (KGF) 在介导预活化 XF-hMSC 的作用中的作用。结果预激活增强了 XF-hMSC 分泌组减少牵张诱导的肺上皮炎症和损伤的能力。预活化的新鲜和冷冻保存的 XF-hMSC 均增强了 VILI 后损伤的消退、恢复氧合、改善肺顺应性、减少肺漏,改善肺结构损伤的解决。最后,预激活的 XF-hMSC 的分泌组增强了上皮伤口修复,部分通过 KGF 依赖性机制。结论 细胞因子预激活增强了冷冻保存的 XF-hMSC 促进 VILI 后损伤缓解的能力,这可能是通过 KGF 依赖性机制实现的。
更新日期:2020-02-05
中文翻译:
冷冻保存的无异种人间充质基质细胞的细胞因子预激活可能通过 KGF 依赖性机制增强呼吸机诱导的肺损伤后的分辨率和修复
背景人类间充质干/基质细胞 (hMSCs) 代表了呼吸机诱导的肺损伤 (VILI) 和急性呼吸窘迫综合征的一种有前景的治疗策略。转化挑战包括在冷冻保存后恢复 hMSC 的功效、开发有效的无异种 (XF) hMSC 以及在临床相关的给药时间点建立真正的治疗潜力。我们希望确定冷冻保存的骨髓来源的 XF-hMSC 的细胞因子预激活是否会增强其在 VILI 后促进损伤解决的能力并阐明作用机制。方法 最初,体外研究检查了细胞因子预激活的 XF-hMSC 的分泌组减轻由循环机械拉伸引起的肺上皮损伤的潜力。之后,麻醉的大鼠接受 VILI 治疗,并在受伤后 6 小时随机接受 1 × 10 7 XF-hMSC/kg,它们是 (i) 幼稚新鲜,(ii) 幼稚冷冻保存,(iii) 细胞因子预活化新鲜或 (iv)细胞因子预活化冷冻保存,而对照动物接受(v)载体。在损伤后 24 小时测量损伤消退的程度。最后,在肺上皮伤口修复模型中确定了角质形成细胞生长因子 (KGF) 在介导预活化 XF-hMSC 的作用中的作用。结果预激活增强了 XF-hMSC 分泌组减少牵张诱导的肺上皮炎症和损伤的能力。预活化的新鲜和冷冻保存的 XF-hMSC 均增强了 VILI 后损伤的消退、恢复氧合、改善肺顺应性、减少肺漏,改善肺结构损伤的解决。最后,预激活的 XF-hMSC 的分泌组增强了上皮伤口修复,部分通过 KGF 依赖性机制。结论 细胞因子预激活增强了冷冻保存的 XF-hMSC 促进 VILI 后损伤缓解的能力,这可能是通过 KGF 依赖性机制实现的。