Bone Marrow Progenitor Cells in Lung Injury and Repair

描述（由申请人提供）： 直到最近，局部干细胞被认为是肺损伤后上皮细胞再生的唯一来源。 然而，越来越多的数据表明骨髓源性干细胞（BMSC）在这一过程中的作用。 这方面的文献很少，主要是轶事。 到目前为止，还没有研究系统地分析干细胞移植到肺的必要条件，甚至没有研究证实这些骨髓来源的细胞是功能性的。 提出这些问题很重要，因为如果得到回答，它们将产生关于如何使用BMSC作为可再生的肺细胞增殖池的信息，并为目前难治性呼吸系统疾病的治疗开辟新的视野。 这样的目标将包括使用同种异体骨髓移植或甚至遗传修饰/外周动员的自体BMSC来治疗呼吸道的遗传性或获得性疾病，例如α-1抗胰蛋白酶缺乏症或肺纤维化。 为了解决这些问题，该基金建议利用Diane Krause博士的赞助来澄清BMSCs在肺修复中的作用。 Krause博士是这一领域的领导者，她成功的指导使她以前的研究员能够追求学术生涯。 本文的目的是研究移植和非移植骨髓成为肺上皮细胞的能力，并确定BMSCs是否可以将功能基因转移到呼吸道上皮细胞。 他们还探索了使用BMSC来调节人类肺部疾病的纤维化小鼠模型中的愈合反应的作用。 这些问题将探讨使用转基因小鼠模型，使用流式细胞术和免疫组化技术，骨髓来源的原位杂交评估，肺细胞的单细胞分析，并在一些生化，分子和功能水平上分析干细胞对肺修复的贡献。

DESCRIPTION (provided by applicant): Until recently, local stem cells were thought to be the sole sources for epithelial repopulation following lung injury. However, an increasing body of data indicates a role for bone marrow derived stem cells (BMSCs) in this process. The scant literature in this area has been largely anecdotal. To date, no study has systematically analyzed the conditions necessary for stem cell to lung engraftment, or even confirmed that these marrow derived cells are functional. Asking these questions is important because, if answered, they will yield information on how to use BMSCs as a renewable pool of pneumocyte precurors and open up new horizons of treatment for currently intractable respiratory disorders. Such a goal would include use of allogeneic marrow transplant or even genetically modified/peripherally mobilized autologous BMSCs to treat inherited or acquired diseases of the respiratory tract such as alpha-1 antitrypsin deficiency or pulmonary fibrosis. To address these issues, this grant proposes to work use the sponsorship of Dr. Diane Krause to clarify the role that BMSCs play in lung repair. Dr. Krause is a leader in this field whose successful mentoring has enabled her previous fellows to pursue academic careers. The aims herein will investigate the capacity of both transplanted and nontransplanted marrow to become lung epithelia and determine if BMSCs can transfer a functional gene to the respiratory epithelium. They also explore a role for the use of BMSCs to modulate the healing response in a fibrotic murine models of human lung disease. These questions will be explored using transgenic mouse models, single cell analysis of pneumocytes using flow cytometry and immunohistochemical techniques, assessment of marrow origin in situ hybridization, and analysis of stem cell contributions to lung repair on a number of biochemical, molecular and functional levels.