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The Stem Cell Niche and Lens Fibrotic Disease

干细胞生态位和晶状体纤维化疾病

基本信息

批准号：
7895599
负责人：
Janice Lynn Walker
金额：
$ 19.31万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895599
关键词：
Antigens Automobile Driving Behavior Biological Models Biological Preservation Blocking Antibodies Bromodeoxyuridine Cadherins Calcium Cataract Cataract Extraction Cell Lineage Cell Proliferation Cell physiology Cell surface Cells Complement Confocal Microscopy Cytometry Development Disease Epiblast Epithelial Cells Etiology Fibrosis Goals Immunofluorescence Immunologic Injury Integrins Label Lead Lens Diseases Lens Opacities Location Magnetism Maintenance Mediating Mesenchymal Modeling Muscle satellite cell Myofibroblast Phenotype Regulation Resolution Role Skeletal Muscle Smooth Muscle Smooth Muscle Actin Staining Method Sorting - Cell Movement Source Stem cells System Techniques Therapeutic Time Vision capsule cell behavior cell motility lens lens capsule lens induction migration precursor cell prevent public health relevance research study response response to injury skeletal src-Family Kinases stem stem cell niche stem cell population wound

项目摘要

DESCRIPTION (provided by applicant): The stem cell niche regulates stem cell function through mechanisms not well understood. We have developed an "ex vivo" culture model system, which allows us the unique ability to study stem/progenitor cell behavior response to injury within their native microenvironment. This system was established as a model for the fibrotic lens disease, Posterior Capsule Opacification, which involves collective migration of lens epithelial cells onto the posterior capsule and the emergence of mesenchymal cells. The etiology of this disease is unknown. Recently, a small subpopulation of myo D/G8 antigen positive epiblast-skeletal muscle stem cells has been identified in the lens. In our "ex vivo" model we have identified a these G8 positive (G8pos) epiblast- skeletal muscle stem cells within a niche nestled among the lens epithelial cells of the equatorial zone (EQ), that remain tightly adherent to the lens capsule after our mock cataract surgery. Upon injury in our "ex vivo" model we detect G8 antigen positive epiblast-skeletal muscle stem/progenitor cells moving from their native microenvironment within the EQ zone to the leading edge of the collectively migrating lens epithelial cells. G8pos skeletal muscle stem/progenitor cells may provide the source of 1-smooth muscle actin positive myofibroblasts detected in lens fibrotic diseases. We hypothesize that disruption of the G8pos epiblast- skeletal muscle stem cell niche, such that could occur during lens injury and cataract surgery, causes the aberrant regulation and emergence of mesenchymal cell precursors that 1) drive the collective migration of the lens epithelial cells for wound closure and 2) transdifferentiate into myofibroblasts causing fibrosis. Our "ex vivo" culture model provides the unique opportunity to ask fundamental questions regarding how reciprocal interactions are regulated within the stem cell niche, such as between niche stem/progenitor cells and their surrounding lens cells, and between the cells in the niche and their matrix microenvironment, all in response to wounding. Elucidation of such mechanisms could not only broaden our understanding of the behavior of a subset of stem/progenitor cells in response to injury-induced changes to their niche but also lead to the development of anti-fibrotic therapeutics to preserve vision. The major goals of this proposal are to 1) Examine the hypothesis that G8pos cells found outside the niche following injury to the lens are derived from amplification of the G8pos epiblast-skeletal muscle stem cell population and/or by recruitment of lens epithelial cells to the G8 lineage. 2) Examine the hypothesis that cadherin-mediated cell-cell and integrin-mediated cell- matrix interactions are critical determinants essential to maintain the normal G8 stem cell niche and are altered upon injury for emergence of G8pos mesenchymal precursor cells. 3) Examine the hypothesis that alterations in the G8pos epiblast skeletal muscle stem cell niche causes the aberrant regulation and emergence of mesenchymal precursors that drive collective migration of lens epithelial cells and ultimately transdifferentiate into myofibroblast. PUBLIC HEALTH RELEVANCE: Lens fibrotic disease causes lens opacities leading to the formation of cataracts which block vision. The exact etiology of lens fibrotic disease is unknown and the long term goals of this project are to understand the role of a subpopulation of G8pos skeletal muscle stem cells, which are located in the lens and emerge from their stem cell niche upon injury, in the induction of lens fibrotic disease. Elucidation of such mechanisms could not only broaden our understanding of stem cell behavior in response to injury-induced changes to their niche but also lead to the development of anti-fibrotic therapeutics to preserve vision.

描述（由申请人提供）：干细胞生态位通过尚未充分了解的机制调节干细胞功能。我们开发了一种“离体”培养模型系统，使我们能够研究干细胞/祖细胞在其天然微环境中对其损伤的行为反应。该系统被建立为纤维化晶状体疾病（后囊混浊）的模型，该疾病涉及晶状体上皮细胞集体迁移到后囊上以及间充质细胞的出现。这种疾病的病因尚不清楚。最近，在晶状体中发现了一小群 myo D/G8 抗原阳性的外胚层骨骼肌干细胞。在我们的“离体”模型中，我们在赤道区（EQ）的晶状体上皮细胞之间的一个小生境中鉴定了这些G8阳性（G8pos）外胚层骨骼肌干细胞，在我们的模拟白内障手术后，它们仍然紧密地粘附在晶状体囊上。在我们的“离体”模型中损伤后，我们检测到 G8 抗原阳性外胚层骨骼肌干/祖细胞从 EQ 区内的天然微环境移动到集体迁移的晶状体上皮细胞的前缘。 G8pos骨骼肌干/祖细胞可能提供在晶状体纤维化疾病中检测到的1-平滑肌肌动蛋白阳性肌成纤维细胞的来源。我们假设，G8pos 外胚层-骨骼肌干细胞生态位的破坏（例如在晶状体损伤和白内障手术期间可能发生）会导致间充质细胞前体的异常调节和出现，从而 1）驱动晶状体上皮细胞集体迁移以实现伤口闭合，2）转分化为肌成纤维细胞，导致纤维化。我们的“离体”培养模型提供了独特的机会来提出有关干细胞生态位内如何调节相互相互作用的基本问题，例如生态位干/祖细胞与其周围晶状体细胞之间，以及生态位中的细胞与其基质微环境之间，所有这些都是对受伤的反应。阐明此类机制不仅可以拓宽我们对干细胞/祖细胞子集响应损伤引起的生态位变化的行为的理解，而且还可以促进抗纤维化疗法的发展以保护视力。该提案的主要目标是 1) 检查以下假设：晶状体损伤后在微环境外发现的 G8pos 细胞源自 G8pos 外胚层骨骼肌干细胞群的扩增和/或通过将晶状体上皮细胞招募到 G8 谱系。 2)检验以下假设：钙粘蛋白介导的细胞-细胞和整合素介导的细胞-基质相互作用是维持正常G8干细胞生态位所必需的关键决定因素，并且在损伤时发生改变以出现G8pos间充质前体细胞。 3) 检查以下假设：G8pos 外胚层骨骼肌干细胞生态位的改变导致间充质前体细胞的异常调节和出现，从而驱动晶状体上皮细胞的集体迁移并最终转分化为肌成纤维细胞。公共健康相关性：晶状体纤维化疾病会导致晶状体混浊，从而导致白内障的形成，从而阻碍视力。晶状体纤维化疾病的确切病因尚不清楚，该项目的长期目标是了解 G8pos 骨骼肌干细胞亚群在诱导晶状体纤维化疾病中的作用，这些干细胞位于晶状体中并在受伤时从其干细胞生态位中出现。阐明此类机制不仅可以拓宽我们对干细胞响应损伤引起的生态位变化的行为的理解，而且还可以促进抗纤维化疗法的发展以保护视力。