Development of a novel humanized mouse model to study bronchopulmonary dysplasia.
Development of a novel humanized mouse model to study bronchopulmonary dysplasia.
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DOI：
10.3389/fped.2023.1146014
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发表时间：
2023
影响因子：
2.6
通讯作者：
中科院分区：
文献类型：
--
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循环中的胎儿单核细胞在支气管肺发育不良中的作用尚不清楚。我们利用支持人类祖细胞植入(MISTRG)的人源化小鼠模型来检验产前单核细胞编程改变早期肺发育和对高氧反应的假设。10只婴儿脐带血来源的单核细胞在P0时(1 × 10~6细胞/只，肝内注射)过继移植到新生MISTRG小鼠体内，然后是常氧和高氧(85%氧气 × 14天)。第14天取肺组织学(肺泡数、周长、面积)和血管参数(vWF染色检测微血管密度、Fulton‘s指数)。用人CD45染色比较造血细胞的存在。比较了安慰剂组和单核细胞注射组的小鼠肺参数。进一步考虑10例患者的个体特征，包括胎龄(GA；n = 2足月，n = 3例中晚期早产儿，n = 5例极早产儿)和先兆子痫(n = 4例)。为探讨这些患者单核细胞微环境的变化，采用多重免疫分析法检测了30种细胞因子/趋化因子在相应人血浆中的含量。在大多数患者和相应的小鼠中，高氧后MISTRG肺泡化得到简化，微血管密度降低。高氧诱导的变化在安慰剂(PBS)和单核细胞注射的小鼠中都可以看到。在常氧条件下，与安慰剂相比，单核细胞对肺泡发育的影响较小(P <； 0.05)。与安慰剂组相比，单核细胞注射组在P14时微血管密度增加(26.7 ± 0.73vs.18.8 ± 1.7血管/肺野；P <； 0.001)。对患者的综合分析显示，在常氧条件下，注射新生儿单核细胞合并低GA和先兆子痫与肺泡化和血管形成的变化有关。这些差异被高氧改变了。CD45+细胞计数与血浆单核细胞趋化蛋白-1(P <； 0.001)、巨噬细胞炎性蛋白-1β(P <； )呈正相关。人CD206和小鼠F4/80的免疫组织化学染色证实，在P14时，MISTRG肺中没有巨噬细胞。尽管在肺发育的早期阶段天生就没有巨噬细胞，但免疫缺陷的MISTRG小鼠显示出由人类单核细胞诱导的肺泡和微血管发育的变化。新生高氧暴露的MISTRG小鼠可作为研究人单核细胞对肺泡和肺血管发育单独作用的新模型。
The role of circulating fetal monocytes in bronchopulmonary dysplasia is not known. We utilized a humanized mouse model that supports human progenitor cell engraftment (MISTRG) to test the hypothesis that prenatal monocyte programming alters early lung development and response to hyperoxia. Cord blood-derived monocytes from 10 human infants were adoptively transferred into newborn MISTRG mice at p0 (1 × 106 cells/mouse, intrahepatic injection) followed by normoxia versus hyperoxia (85% oxygen × 14 days). Lungs were harvested at p14 for alveolar histology (alveolar count, perimeter and area) and vascular parameters (vWF staining for microvessel density, Fulton's index). Human CD45 staining was conducted to compare presence of hematopoietic cells. Murine lung parameters were compared among placebo and monocyte-injected groups. The individual profiles of the 10 patients were further considered, including gestational age (GA; n = 2 term, n = 3 moderate/late preterm, and n = 5 very preterm infants) and preeclampsia (n = 4 patients). To explore the monocyte microenvironment of these patients, 30 cytokines/chemokines were measured in corresponding human plasma by multiplex immunoassay. Across the majority of patients and corresponding mice, MISTRG alveolarization was simplified and microvessel density was decreased following hyperoxia. Hyperoxia-induced changes were seen in both placebo (PBS) and monocyte-injected mice. Under normoxic conditions, alveolar development was altered modestly by monocytes as compared with placebo (P < 0.05). Monocyte injection was associated with increased microvessel density at P14 as compared with placebo (26.7 ± 0.73 vs. 18.8 ± 1.7 vessels per lung field; P < 0.001). Pooled analysis of patients revealed that injection of monocytes from births complicated by lower GA and preeclampsia was associated with changes in alveolarization and vascularization under normoxic conditions. These differences were modified by hyperoxia. CD45+ cell count was positively correlated with plasma monocyte chemoattractant protein-1 (P < 0.001) and macrophage inflammatory protein-1β (P < 0.01). Immunohistochemical staining for human CD206 and mouse F4/80 confirmed absence of macrophages in MISTRG lungs at P14. Despite the inherent absence of macrophages in early stages of lung development, immunodeficient MISTRG mice revealed changes in alveolar and microvascular development induced by human monocytes. MISTRG mice exposed to neonatal hyperoxia may serve as a novel model to study isolated effects of human monocytes on alveolar and pulmonary vascular development.
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影响因子：
2.6
作者：
Chaudhury, Sonali;Saqibuddin, Juanita;Mestan, Karen K.
通讯作者：
Mestan, Karen K.
影响因子：
2.7
作者：
Hu, Yu;Fu, Jianhua;Xue, Xindong
通讯作者：
Xue, Xindong
影响因子：
3.8
作者：
Mestan, K. K.;Check, J.;Ernst, L. M.
通讯作者：
Ernst, L. M.
影响因子：
7.4
作者：
Hummitzsch L;Berndt R;Kott M;Rusch R;Faendrich F;Gruenewald M;Steinfath M;Albrecht M;Zitta K
通讯作者：
Zitta K
DOI：
10.1164/rccm.200902-0242oc
发表时间：
2009-12-01
影响因子：
24.7
作者：
Aslam, Muhammad;Baveja, Rajiv;Kourembanas, Stella
通讯作者：
Kourembanas, Stella