Autophagy regulates the therapeutic potential of adipose-derived stem cells in LPS-induced pulmonary microvascular barrier damage
Autophagy regulates the therapeutic potential of adipose-derived stem cells in LPS-induced pulmonary microvascular barrier damage
复制标题
自噬调节脂肪干细胞在 LPS 诱导的肺微血管屏障损伤中的治疗潜力
DOI：
10.1038/s41419-019-2037-8
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发表时间：
2019-10-23
影响因子：
9
通讯作者：
Zhang, Dan
中科院分区：
文献类型：
--
作者：
Li, Chichi;Pan, Jingye;Zhang, Dan
脂肪源性干细胞（ADSCs）已被证明对一些肺部疾病有益，旁分泌效应是基于ADSCs的治疗的主要机制。自噬在维持干细胞稳态和存活中起着至关重要的作用。然而，自噬在ADSC旁分泌作用中的作用尚未完全阐明。我们研究了ADSCs是否以旁分泌方式参与脂多糖（LPS）诱导的肺微血管内皮细胞（PMVEC）屏障损伤，并阐明了自噬在调节ADSC旁分泌作用中的作用。将自噬抑制或不自噬抑制的pmvec和ADSCs在不进行细胞间接触的情况下共培养，并在LPS处理后评估微血管屏障功能。通过检测内皮细胞的必需生长因子来评估ADSC旁分泌功能。在体内实验中，将具有或不具有自噬抑制的ADSCs移植到lps诱导的肺损伤小鼠中，并评估肺损伤。ADSCs明显减轻lps诱导的微血管屏障损伤。此外，LPS处理可诱导ADSC旁分泌VEGF、FGF和EGF水平，特别是在共培养条件下。抑制自噬削弱了旁分泌功能和ADSCs对微血管屏障损伤的保护作用。此外，ADSC移植减轻了lps诱导的肺损伤，抑制自噬明显削弱了ADSC对肺损伤的治疗作用。总之，这些发现表明ADSC旁分泌效应在lps诱导的肺微血管屏障损伤中起重要的保护作用。自噬在旁分泌过程中起着积极的调节作用。这些结果有助于阐明ADSC旁分泌效应在急性肺损伤中的作用和机制，并有助于开发有效的治疗方法。
Adipose-derived stem cells (ADSCs) have been shown to be beneficial in some pulmonary diseases, and the paracrine effect is the major mechanism underlying ADSC-based therapy. Autophagy plays a crucial role in maintaining stem cell homeostasis and survival. However, the role of autophagy in mediating ADSC paracrine effects has not been thoroughly elucidated. We examined whether ADSCs participate in lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cell (PMVEC) barrier damage in a paracrine manner and illuminated the role of autophagy in regulating ADSC paracrine effects. PMVECs and ADSCs with or without autophagy inhibition were cocultured without intercellular contact, and the microvascular barrier function was assessed after LPS treatment. ADSC paracrine function was evaluated by detecting essential growth factors for endothelial cells. For in vivo experiments, ADSCs with or without autophagy inhibition were transplanted into LPS-induced lung-injury mice, and lung injury was assessed. ADSCs significantly alleviated LPS-induced microvascular barrier injury. In addition, ADSC paracrine levels of VEGF, FGF, and EGF were induced by LPS treatment, especially in the coculture condition. Inhibiting autophagy weakened the paracrine function and the protective effects of ADSCs on microvascular barrier injury. Moreover, ADSC transplantation alleviated LPS-induced lung injury, and inhibiting autophagy markedly weakened the therapeutic effect of ADSCs on lung injury. Together, these findings show that ADSC paracrine effects play a vital protective role in LPS-induced pulmonary microvascular barrier injury. Autophagy is a positive mediating factor in the paracrine process. These results are helpful for illuminating the role and mechanism of ADSC paracrine effects and developing effective therapies in acute lung injury.