Impaired Angiogenic Supportive Capacity and Altered Gene Expression Profile of Resident CD146+ Mesenchymal Stromal Cells Isolated from Hyperoxia-Injured Neonatal Rat Lungs
Impaired Angiogenic Supportive Capacity and Altered Gene Expression Profile of Resident CD146+ Mesenchymal Stromal Cells Isolated from Hyperoxia-Injured Neonatal Rat Lungs
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DOI：
10.1089/scd.2017.0145
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发表时间：
2018-06-29
影响因子：
4
通讯作者：
Thebaud, Bernard
中科院分区：
文献类型：
--
作者：
Collins, Jennifer J. P.;Lithopoulos, Marissa A.;Thebaud, Bernard
支气管肺发育不良（BPD）是极早产最常见的并发症，可由氧相关性肺损伤引起，其特征是肺泡和血管发育受损。骨髓间充质干细胞（Mesenchymal stromal cells，MSCs）具有肺保护作用。相反，BPD与气管抽吸物中MSC的增加相关。我们假设内源性肺（L-）间充质干细胞在一个完善的氧气诱导的大鼠模型模仿BPD功能的扰动。从出生到出生后第10天，幼鼠暴露于21%或95%的氧气中。在第12天，分离CD 146（+）L-MSC，并根据国际细胞治疗学会标准进行表征。采用划痕法和内皮细胞网络形成法检测内皮细胞和血管的修复能力，采用混合淋巴细胞反应法检测免疫功能。微阵列分析使用Affyssin GeneChip和基因集富集分析软件进行。从暴露于高氧的大鼠幼仔中分离的CD 146（+）L-MSCs降低了CD 73的表达并抑制了肺内皮网络的形成。CD 146（+）L-MSCs无差别地促进上皮伤口愈合和限制T细胞增殖。在体内高氧后，轴突导向因子和CDC 42通路的有效抗血管生成基因的表达增加，而抗炎Janus激酶（JAK）/信号转导和转录激活因子（STAT）和肺/血管生长促进成纤维细胞生长因子（FGF）通路的基因减少。总之，体内高氧暴露改变了L-MSCs的促血管生成作用和FGF表达。此外，CD 73和JAK/STAT表达降低表明免疫功能降低。L-MSC功能可能受到干扰并导致BPD发病。这些发现可能导致在制造具有上级修复能力的外源性MSC方面的改进。
Bronchopulmonary dysplasia (BPD), the most common complication of extreme preterm birth, can be caused by oxygen-related lung injury and is characterized by impaired alveolar and vascular development. Mesenchymal stromal cells (MSCs) have lung protective effects. Conversely, BPD is associated with increased MSCs in tracheal aspirates. We hypothesized that endogenous lung (L-)MSCs are perturbed in a well-established oxygen-induced rat model mimicking BPD features. Rat pups were exposed to 21% or 95% oxygen from birth to postnatal day 10. On day 12, CD146(+) L-MSCs were isolated and characterized according to the International Society for Cellular Therapy criteria. Epithelial and vascular repair potential were tested by scratch assay and endothelial network formation, respectively, immune function by mixed lymphocyte reaction assay. Microarray analysis was performed using the Affymetrix GeneChip and gene set enrichment analysis software. CD146(+) L-MSCs isolated from rat pups exposed to hyperoxia had decreased CD73 expression and inhibited lung endothelial network formation. CD146(+) L-MSCs indiscriminately promoted epithelial wound healing and limited T cell proliferation. Expression of potent antiangiogenic genes of the axonal guidance cue and CDC42 pathways was increased after in vivo hyperoxia, whereas genes of the anti-inflammatory Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and lung/vascular growth-promoting fibroblast growth factor (FGF) pathways were decreased. In conclusion, in vivo hyperoxia exposure alters the proangiogenic effects and FGF expression of L-MSCs. In addition, decreased CD73 and JAK/STAT expression suggests decreased immune function. L-MSC function may be perturbed and contribute to BPD pathogenesis. These findings may lead to improvements in manufacturing exogenous MSCs with superior repair capabilities.