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，骨髓来源的干细胞(BMSCs)在这一过程中发挥了作用。这方面的文献很少，很大程度上是轶事。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有功能的。问这些问题很重要，因为如果得到回答，它们将提供如何将BMSCs用作可再生的肺细胞前体细胞池的信息，并为目前难治的呼吸系统疾病开辟新的治疗视野。这一目标将包括使用异基因骨髓移植，甚至使用转基因/外周动员的自体骨髓间充质干细胞来治疗遗传性或获得性呼吸道疾病，如α-1抗胰蛋白酶缺乏症或肺纤维化。 为了解决这些问题，这笔赠款建议利用Diane Krause博士的赞助来澄清BMSCs在肺修复中所起的作用。克劳斯博士是这一领域的领军人物，她的成功指导使她之前的同事能够追求学术生涯。本文的目的是研究移植和未移植的骨髓成为肺上皮细胞的能力，并确定骨髓间充质干细胞是否能将功能基因转移到呼吸道上皮细胞。他们还探索了使用骨髓间充质干细胞在人类肺部疾病纤维化小鼠模型中调节愈合反应的作用。这些问题将通过转基因小鼠模型、使用流式细胞仪和免疫组织化学技术对肺泡细胞进行单细胞分析、评估骨髓来源的原位杂交以及在一些生化、分子和功能水平上分析干细胞对肺修复的贡献来探索。

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.