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Embryonic stem cell-based fibroblast model of innate immunity development

基于胚胎干细胞的先天免疫发育成纤维细胞模型

基本信息

批准号：
8772372
负责人：
YAN-LIN GUO
金额：
$ 35.41万
依托单位：
UNIVERSITY OF SOUTHERN MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8772372
关键词：
Active immunity Affect Bacterial Infections Biological Models Cell Culture Techniques Cell Transplants Cells Cellular biology Development Embryonic Development Endotoxins Engineering Failure Fibroblasts Generations Genetic Transcription Human IRF3 gene Immune Immune response Immunity Immunization Immunologic Adjuvants Implant In Vitro Infectious Agent Inflammatory Inflammatory Response Interferon Type I Interferon-alpha Interferon-beta Interferons Lead Lipopolysaccharides Medical Methods Modeling Molecular Mus Natural Immunity Organism Patients Play Receptor Activation Regenerative Medicine Research Role Site Source Stem Cell Research Stem cells Stimulus Study models Testing Time Tissues Virus Diseases Work analog base clinical application comparative connective tissue growth factor cytokine embryonic stem cell expectation human disease improved in vitro Model in vivo in vivo Model method development mouse model novel novel strategies pathogen public health relevance research study response stem cell differentiation transcription factor viral RNA wound

项目摘要

DESCRIPTION (provided by applicant): Embryonic stem cells (ESCs) are considered a promising cell source for regenerative medicine. Intensive research over the past decade has led to the possibility that ESC-differentiated cells (ESC-DCs) could be used for the treatment of human diseases. However, increasing evidence indicates that ESC-DCs generated by the current differentiation methods are not fully functional. Recent studies indicate that ESC-DCs lack innate immunity to a wide range of infectious agents. When used in the patient, ESC-DCs would be placed in a wound site that is exposed to various pathogens and inflammatory cytokines; therefore, their viability and functionality could be compromised if the cells do not have competent immunity. We recently demonstrated that ESCs are intrinsically deficient in expressing type-I IFN and inflammatory cytokines. This finding explains the lack of innate immunity in ESC-DCs and has led to our central hypothesis that innate immunity is not developed in ESCs and cannot be effectively induced by current methods of differentiation, but it could be induced if proper "immunostimulation" is provided during differentiation. The proposed study aims to understand the molecular mechanisms that control innate immunity and to develop differentiation strategies that generate ESC-DCs with competent immunity. Fibroblasts (FBs) are major cells that play key roles in tissue formation and in modulating tissue immune/inflammatory responses. Using ESC-differentiated FBs (ESC-FBs) as a model system, we will determine the molecular basis for innate immunity deficiency in ESCs and identify the factors that stimulate innate immunity development (aim 1). We will then develop novel strategies that utilize IFN?, viral RNA analogs, and lipopolysaccharide as "immunostimulants" to promote innate immunity during differentiation (aim 2). The innate immunity of ESC-FBs will be comparatively analyzed with naturally differentiated FBs by in vitro models and will be evaluated with a syngeneic mouse in vivo model, where immune and inflammatory responses in implanted ESC-FBs will be assessed after the host is challenged with bacterial and viral infections (aim 3). We expect that the results will lead to the development of differentiation strategies that could fundamentally transform the current methods and achieve a better understanding of mechanisms that control innate immunity development during embryogenesis.

描述(申请人提供)：胚胎干细胞(ESCs)被认为是再生医学的一个很有前途的细胞来源。过去十年的深入研究使干细胞分化细胞(ESC-DC)有可能用于治疗人类疾病。然而，越来越多的证据表明，目前的分化方法所产生的ESC-DC并不是完全功能的。最近的研究表明，ESC-DC缺乏对多种感染源的天然免疫力。当用于患者时，ESC-DC会被放置在暴露于各种病原体和炎性细胞因子的伤口部位；因此，如果细胞没有足够的免疫力，它们的活性和功能可能会受到影响。我们最近证实，胚胎干细胞在表达I型干扰素和炎性细胞因子方面存在先天缺陷。这一发现解释了ESC-DC缺乏天然免疫的原因，并导致了我们的中心假设，即ESC不能发育，并且不能用现有的分化方法有效地诱导，但如果在分化过程中提供适当的“免疫刺激”，它可以被诱导。这项拟议的研究旨在了解控制先天免疫的分子机制，并开发分化策略，以产生具有足够免疫力的ESC-DC。成纤维细胞是在组织形成和调节组织免疫/炎症反应中起关键作用的主要细胞。我们将以胚胎干细胞分化的胎牛血清(ESC-FBS)作为模型系统，确定胚胎干细胞先天免疫缺陷的分子基础，并确定刺激先天免疫发育的因素(目标1)。然后，我们将开发新的策略，利用干扰素、病毒RNA类似物和脂多糖作为“免疫刺激剂”来促进分化过程中的先天免疫(目标2)。ESC-FBS的天然免疫功能将通过体外模型与自然分化的FBS进行比较分析，并将用同基因小鼠体内模型进行评估，其中植入的ESC-FBS将在宿主受到细菌和病毒感染后评估免疫和炎症反应(目标3)。我们预计，这些结果将导致分化策略的发展，这些策略可以从根本上改变目前的方法，并更好地理解胚胎发育过程中控制先天性免疫发育的机制。