Sammour Ibrahim, Somashekar Santhosh, Huang Jian, Batlahally Sunil, Breton Matthew, Valasaki Krystalenia, Khan Aisha, Wu Shu, Young Karen C
Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.
Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
PLoS One. 2016 Oct 6;11(10):e0164269. doi: 10.1371/journal.pone.0164269. eCollection 2016.
Mesenchymal stem cells (MSC) improve alveolar and vascular structures in experimental models of bronchopulmonary dysplasia (BPD). Female MSC secrete more anti-inflammatory and pro-angiogenic factors as compared to male MSC. Whether the therapeutic efficacy of MSC in attenuating lung injury in an experimental model of BPD is influenced by the sex of the donor MSC or recipient is unknown. Here we tested the hypothesis that female MSC would have greater lung regenerative properties than male MSC in experimental BPD and this benefit would be more evident in males.
To determine whether intra-tracheal (IT) administration of female MSC to neonatal rats with experimental BPD has more beneficial reparative effects as compared to IT male MSC.
Newborn Sprague-Dawley rats exposed to normoxia (RA) or hyperoxia (85% O2) from postnatal day (P) 2- P21 were randomly assigned to receive male or female IT bone marrow (BM)-derived green fluorescent protein (GFP+) MSC (1 x 106 cells/50 μl), or Placebo on P7. Pulmonary hypertension (PH), vascular remodeling, alveolarization, and angiogenesis were assessed at P21. PH was determined by measuring right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling was evaluated by quantifying the percentage of muscularized peripheral pulmonary vessels. Alveolarization was evaluated by measuring mean linear intercept (MLI) and radial alveolar count (RAC). Angiogenesis was determined by measuring vascular density. Data are expressed as mean ± SD, and analyzed by ANOVA.
There were no significant differences in the RA groups. Exposure to hyperoxia resulted in a decrease in vascular density and RAC, with a significant increase in MLI, RVSP, and the percentage of partially and fully muscularized pulmonary arterioles. Administration of both male and female MSC significantly improved vascular density, alveolarization, RVSP, percent of muscularized vessels and alveolarization. Interestingly, the improvement in PH and vascular remodeling was more robust in the hyperoxic rodents who received MSC from female donors. In keeping with our hypothesis, male animals receiving female MSC, had a greater improvement in vascular remodeling. This was accompanied by a more significant decrease in lung pro-inflammatory markers and a larger increase in anti-inflammatory and pro-angiogenic markers in male rodents that received female MSC. There were no significant differences in MSC engraftment among groups.
Female BM-derived MSC have greater therapeutic efficacy than male MSC in reducing neonatal hyperoxia-induced lung inflammation and vascular remodeling. Furthermore, the beneficial effects of female MSC were more pronounced in male animals. Together, these findings suggest that female MSC maybe the most potent BM-derived MSC population for lung repair in severe BPD complicated by PH.
间充质干细胞（MSC）可改善支气管肺发育不良（BPD）实验模型中的肺泡和血管结构。与雄性MSC相比，雌性MSC分泌更多的抗炎和促血管生成因子。供体MSC或受体的性别是否会影响MSC在BPD实验模型中减轻肺损伤的治疗效果尚不清楚。在此，我们检验了以下假设：在实验性BPD中，雌性MSC比雄性MSC具有更强的肺再生特性，且这种益处在雄性中更为明显。
确定与气管内（IT）给予雄性MSC相比，给患有实验性BPD的新生大鼠气管内给予雌性MSC是否具有更有益的修复作用。
将出生后第2天至第21天暴露于常氧（RA）或高氧（85% O₂）环境的新生Sprague-Dawley大鼠随机分为接受雄性或雌性IT骨髓（BM）来源的绿色荧光蛋白（GFP+）MSC（1×10⁶个细胞/50 μl）组，或在第7天接受安慰剂组。在第21天评估肺动脉高压（PH）、血管重塑、肺泡化和血管生成。通过测量右心室收缩压（RVSP）来确定PH，并通过量化外周肺血管肌化百分比来评估肺血管重塑。通过测量平均线性截距（MLI）和放射状肺泡计数（RAC）来评估肺泡化。通过测量血管密度来确定血管生成。数据以平均值±标准差表示，并通过方差分析进行分析。
RA组之间无显著差异。暴露于高氧导致血管密度和RAC降低，MLI、RVSP以及部分和完全肌化的肺小动脉百分比显著增加。给予雄性和雌性MSC均显著改善了血管密度、肺泡化、RVSP、肌化血管百分比和肺泡化。有趣的是，在接受雌性供体MSC的高氧啮齿动物中，PH和血管重塑的改善更为显著。与我们的假设一致，接受雌性MSC的雄性动物在血管重塑方面有更大改善。这伴随着接受雌性MSC的雄性啮齿动物肺促炎标志物的更显著降低以及抗炎和促血管生成标志物的更大增加。各组之间MSC植入无显著差异。
雌性BM来源的MSC在减轻新生儿高氧诱导的肺炎症和血管重塑方面比雄性MSC具有更强的治疗效果。此外，雌性MSC的有益作用在雄性动物中更为明显。总之，这些发现表明，对于合并PH的严重BPD，雌性MSC可能是最有效的BM来源的MSC群体用于肺修复。
