Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function

微环境对干细胞可塑性和功能的表观遗传效应

• 批准号: 7684203
• 负责人: MARY J.C. HENDRIX
• 金额: $ 12.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7684203
• 关键词: 3-Dimensional; Affect; Biocompatible Materials; Biological; Blood Vessels; Cells; Characteristics; Communication; Complex; Cues; Development; Embryo; Epigenetic Process; Gene Proteins; Genes; Genotype; Goals; Human; Image Analysis; In Situ; Knowledge; Laboratories; Lasers; Limb structure; Maintenance; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Metastatic to; Microdissection; Modeling; Molecular; Mus; Phenotype; Pigmentation physiologic function; Plastics; Play; Population; Property; Qualifying; Regulatory Pathway; Research; Research Personnel; Role; Stem cells; Study models; Testing; Therapeutic; Tissues; Translating; Wound Healing; Zebrafish; base; cancer cell; cancer stem cell; cell type; comparative; concept; design; extracellular; human embryonic stem cell; in vivo; insight; melanocyte; melanoma; neoplastic cell; novel; novel therapeutics; precursor cell; programs; therapeutic target; transdifferentiation; tumor progression

A dynamic, complex relationship exists between stem cells and their microenvironment, which plays a pivotal role in cell fate determination. Key to identifying the molecular mechanisms underlying stem cell plasticity, is understanding the unique epigenetic role of the microenvironment on the emergence of cell phenotype. Previous studies from our laboratory have revealed the unexpected finding that metastatic human melanoma cells express multiple cellular phenotypes and their respective precursor cells, suggesting a dedifferentiated cancer cell with a phenotype characteristic of stem cells. Additional evidence supporting the concept of tumor cell plasticity includes: the demonstration of human metastatic melanoma cells forming vasculogenic- like networks with the simultaneous expression of endothelial-specific genes; developing chimeric blood vessels in an ischemic mouse limb model; and initiating the formation of tissues in an embryonic zebrafish model. Furthermore, recent preliminary findings indicate the powerful influence of a metastatic melanoma microenvironment with respect to inducing transdifferentiation of normal melanocytes into an aggressive tumor cell phenotype ~ when exposed to this metastatic milieu. Most interestingly, preliminary findings with human embryonic stem cells (hESCs) exposed to a metastatic microenvironment reveal their differentiation to a highly migratory phenotype; while the microenvironment associated with hESCs reverts amelanotic metastatic melanoma cells to a melanocyte-like phenotype with pigmentation. Therefore, based on these intriguing observations, we propose to test the central hypothesis that the microenvironment associated with stem cells -- representative of hESCs. cancer stem cells, and normal epidermal stem cells -- contains informational cues with the potential to epigeneticallv reprogram the genotype and phenotype of cells exposed to it. Using unique. 3-D organotypic models and zebrafish embryos, together with functional analysis, imaging, laser microdissection. and global gene analysis, we propose to: Aim 1: Determine the comparative epigenetic effects of the 3-D microenvironments associated with hESCs, cancer stem cells (primarily melanoma), and normal epidermal stem cells for their potential to reprogram the genotype and phenotype of specific stem cell populations. Aim 2: Identify the molecular basis for the epigenetic reprogramming of the genotype and phenotype of the affected stem cell populations exposed to various 3-D microenvironments. Aim 3: Investigate the developmental plasticity of the embryonic, cancer and normal epidermal stem cells in an embryonic zebrafish model - to determine the biological relevance of key regulatory pathways involved in the control of cellular phenotype and cell fate determinations. At the completion of these studies, we expect to gain novel insights into the differences in inductive properties of the respective microenvironment(s) of these stem cells that could be translated for novel therapeutic targets.

干细胞与其微环境之间存在着动态的、复杂的关系， 决定细胞命运的作用。识别干细胞可塑性的分子机制的关键是 了解微环境对细胞表型出现的独特表观遗传作用。 我们实验室以前的研究揭示了一个意想不到的发现， 细胞表达多种细胞表型和它们各自的前体细胞，这表明去分化 具有干细胞表型特征的癌细胞。支持以下概念的其他证据 肿瘤细胞可塑性包括：人转移性黑色素瘤细胞形成血管生成的证明， 同时表达内皮特异性基因的类似网络;开发嵌合血液 血管;以及在胚胎斑马鱼中启动组织的形成 模型此外，最近的初步研究结果表明，转移性黑色素瘤的强大影响， 在诱导正常黑素细胞转分化为侵袭性黑素细胞方面， 肿瘤细胞表型-当暴露于这种转移性环境时。最有趣的是，初步调查结果， 暴露于转移性微环境的人胚胎干细胞（hESC）揭示其分化 高度迁移的表型;而与hESC相关的微环境恢复无黑色素表型， 转移性黑色素瘤细胞转化为具有色素沉着的黑色素细胞样表型。因此，根据这些 有趣的观察，我们建议测试的核心假设，即微环境与 干细胞--hESC的代表。癌干细胞和正常表皮干细胞 具有表观遗传学重编程细胞基因型和表型潜力的信息线索 暴露在其中。使用独特的。3-D器官型模型和斑马鱼胚胎，以及功能 分析成像激光显微切割和全局基因分析，我们建议：目标1：确定 与hESC、癌症干细胞相关的三维微环境的比较表观遗传效应 （主要是黑色素瘤）和正常表皮干细胞，因为它们具有重新编程基因型的潜力， 特定干细胞群体的表型。目的2：确定表观遗传的分子基础 受影响的干细胞群体的基因型和表型的重编程暴露于各种3-D 微环境目的3：探讨胚胎、肿瘤和正常人的发育可塑性 表皮干细胞在胚胎斑马鱼模型-以确定关键的生物相关性 参与细胞表型控制和细胞命运决定的调节途径。在 这些研究的完成，我们希望获得新的见解的差异，电感性质的 这些干细胞各自的微环境可以被转化为新的治疗靶点。