Mesenchymal Stem Cells in the Treatment of Lung Fibrosis

间充质干细胞治疗肺纤维化

• 批准号: 6989396
• 负责人: Luis Alberto Ortiz
• 金额: $ 34.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989396
• 关键词: CD44 molecule; bone marrow; bone morphogenetic proteins; cell differentiation; cell population study; fibroblast growth factor; idiopathic pulmonary fibrosis; laboratory mouse; mesenchyme; nonhuman therapy evaluation; osteopontin; protein protein interaction; pulmonary fibrosis /granuloma; respiratory epithelium; stem cell transplantation; stem cells

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis is a crippling disease characterized by high mortality. Stem cell based therapies may represent a viable alternative to repair injured lung. Our laboratory has developed a reliable method based on immunodepletion to isolate mesenchymal stem cells (MSCs) from the bone marrow of mice. MSC engraft in mouse lung, adopt alveolar epithelial (AE) type II cell phenotype, and significantly reduced the extent of inflammation and collagen deposition in response to bleomycin. MSC are characterized by their uniform expression of the CD44 antigen. CD44 is a receptor for osteopontin (OPN). Expressed at low levels in normal lung, OPN expression is greatly enhanced during lung injury and therefore, interactions between CD44 and OPN may play an important role in mediating the extent and anatomical location of MSC engraftment in lung. Following lung engraftment MSCs adopt AE type II phenotype. Whether this is the result of cell fusion or the product of a highly regulated cell differentiation program is unknown. MSCs undergo epithelial differentiation in vitro and our data has shown that this process is associated suppression of FGF2, a mitogen for MSCs, and sequential activation of the BMP receptors IA and IB. Activation of BMPR-IA instructs stem cells to commit to a particular fate and induces expression of BMPR-IB, activation of which then promotes terminal differentiation. MSCs constitutively express BMPR-IA but lack expression of BMPR-IB. We hypothesize that inhibition of FGF2 facilitates expression of BMPR-IB and promotes epithelial MSC differentiation. In addition, we hypothesize that under non-inflammatory conditions MSC engraftment may be enhanced and targeted to the lung epithelium by inducing the controlled expression of osteopontin. Finally, we postulate that exogenously administered MSCs engraft in the lung and ameliorate lung injury. Thus, MSCs may be manipulated to deliver therapeutic genes to the injured lung. To test these hypotheses we propose the following specific aims: 1) To determine the molecular mechanism that regulates differentiation of MSCs into epithelial cell fate. 2) To determine the role that CD44/osteopontin interactions play during MSC engraftment in the mouse lung. 3) To determine whether or not the systemic administration of MSCs can be used to ameliorate the fibroproliferative responses observed in the injured lung.

描述（由申请人提供）：特发性肺纤维化是一种以高死亡率为特征的致残性疾病。基于干细胞的疗法可能是修复受损肺部的可行替代方案。我们的实验室开发了一种基于免疫耗竭的可靠方法，从小鼠骨髓中分离间充质干细胞（MSC）。 MSC 植入小鼠肺中，采用肺泡上皮 (AE) II 型细胞表型，并显着减少对博莱霉素的反应炎症程度和胶原沉积。 MSC 的特点是一致表达 CD44 抗原。 CD44 是骨桥蛋白 (OPN) 的受体。 OPN 在正常肺中表达水平较低，但在肺损伤期间表达大大增强，因此 CD44 和 OPN 之间的相互作用可能在介导 MSC 在肺中植入的程度和解剖位置方面发挥重要作用。肺移植后 MSC 采用 AE II 型表型。这是细胞融合的结果还是高度调控的细胞分化程序的产物尚不清楚。 MSC 在体外经历上皮分化，我们的数据表明该过程与 FGF2（MSC 的有丝分裂原）的抑制以及 BMP 受体 IA 和 IB 的连续激活相关。 BMPR-IA 的激活指示干细胞致力于特定的命运并诱导 BMPR-IB 的表达，其激活然后促进终末分化。 MSC 组成型表达 BMPR-IA，但缺乏 BMPR-IB 表达。我们假设抑制 FGF2 会促进 BMPR-IB 的表达并促进上皮 MSC 分化。此外，我们假设在非炎症条件下，通过诱导骨桥蛋白的受控表达，可以增强间充质干细胞的植入并靶向肺上皮。最后，我们假设外源性 MSC 植入肺部并改善肺损伤。因此，可以操纵间充质干细胞将治疗基因传递到受损的肺部。为了检验这些假设，我们提出以下具体目标：1）确定调节 MSC 分化为上皮细胞命运的分子机制。 2) 确定 CD44/骨桥蛋白相互作用在 MSC 植入小鼠肺过程中发挥的作用。 3) 确定间充质干细胞的全身给药是否可用于改善受损肺中观察到的纤维增殖反应。