Multipotent lung mesenchymal cells in neonatal lung injury

我们已经获得的试点数据表明，气管吸出物从一周大的早产儿， 因呼吸窘迫综合征（RDS）接受机械通气的患者含有集落形成成纤维细胞- 如具有间充质干细胞中典型的表面标记和分化潜能的细胞。的 细胞对Stro-1、CD 73、CD 90、CD 105和CD 166呈阳性，但对CD 34、CD 45和CD 11b呈阴性， 表明它们是基质来源而不是造血来源。此外，它们表现出大量的增殖性 能力并能够分化成骨细胞、脂肪细胞和肌成纤维细胞。调节 来自这些细胞的培养基增强上皮生长和修复，抑制鳞状分化， 含有碱性成纤维细胞生长因子（bFGF/FGF-2）、角质形成细胞生长因子（KGF）和血管生成因子（VEGF）。 内皮细胞生长因子（VEGF）。最后，分离多能间充质细胞， 呼吸窘迫综合征早产儿的气管吸出物与长期的 补充O2和慢性肺病的发展，即，支气管肺发育不良（BPD）。我们 因此，假设多能肺间充质细胞参与新生儿肺修复和区域 肺损伤的生物标志物。为了验证这个假设，我们提出了以下具体目标。 具体目标1。确定多能肺间充质细胞从 早产儿被招募到空域。我们假设上皮损伤诱导 bFGF和单核细胞趋化蛋白（MCP）-1的表达，从而促进肺间质 细胞迁移到大气层。 具体目标2。描述多能肺间充质细胞 细胞参与肺修复。我们推测：1）肺间充质细胞产生营养因子 能够促进呼吸道上皮修复; 2）当被转化生长因子（TGF）-β 1刺激时， 肺间充质细胞分化成肌成纤维细胞，从而促进血管生成和纤维形成。 具体目标3。多能肺间充质细胞的存在与早产儿 患有慢性肺部疾病的婴儿。我们假设多能的 肺间充质细胞是肺损伤和持续性肺功能障碍的生物标志物。我们将 前瞻性比较早产儿多能肺间充质干细胞移植的临床结局， 细胞已经与那些细胞未被分离的细胞分离，集中在呼吸系统 依从性和吸氧天数。 了解多能肺间充质细胞在BPD发病机制中的作用将导致 这种疾病的治疗方法的改进。__

We have obtained pilot data demonstrating that tracheal aspirates from week-old premature infants undergoing mechanical ventilation for respiratory distress syndrome (RDS) contain colony-forming fibroblast- like cells with surface markers and differentiation potential typically found in mesenchymal stem cells. The cells are positive for Stro-1, CD73, CD90, CD105 and CD166, but negative for CD34, CD45 and CD11b, suggesting that they are of stromal but not hematopoietic origin. Further, they exhibit ample proliferative capacity and are capable of differentiation into osteocytes, adipocytes and myofibroblasts. Conditioned medium from these cells enhances epithelial growth and repair, inhibits squamous differentiation and contains basic fibroblast growth factor (bFGF/FGF-2), keratinocyte growth factor (KGF) and vascular endothelial cell growth factor (VEGF). Finally, the isolation of multipotent mesenchymal cells from the tracheal aspirates of premature infants with RDS is associated with a prolonged requirement for supplemental 02 and the development of chronic lung disease, i.e., bronchopulmonary dysplasia (BPD). We therefore hypothesize that multipotent lung mesenchymal cells participate in neonatal lung repair and area biomarker for lung injury. To test this general hypothesis, we propose the following Specific Aims. Specific Aim 1. Determine mechanisms by which multipotent lung mesenchymal cells from premature infants are recruited to the airspaces. Wehypothesize that epithelial injury induces expression ofbFGF and monocyte chemoattractant protein (MCP)-1, thereby promoting lung mesenchymal cell migration to the airspaces. Specific Aim 2. Characterize potential mechanisms by which multipotent lung mesenchymal cells participate in lung repair. Wehypothesize that: 1)lung mesenchymal cells produce trophic factors capable of promoting respiratory epithelial repair; 2) when stimulated by transforming growth factor (TGF)-fl, lung mesenchymal cells differentiate into myofibroblasts, thereby promoting angiogenesis and fibrogenesis. Specific Aim 3. Correlate the presence of multipotent lung mesenchymal cells in premature infants with the development and severity of chronic lung disease. Wehypothesize that multipotent lung mesenchymal cells are biomarkers for lung injury andpersistent pulmonary dysfunction. We will prospectively compare the clinical outcomes of premature infants from whom multipotent lung mesenchymal cells have been isolated with those from whom cells are not isolated, focusing on respiratory system compliance and days of oxygen supplementation. Understanding the role of multipotent lung mesenchymal cells in the pathogenesis of BPDwill lead to improvements in thetreatment of this disease. __