Control of Hematopoietic Differentiation by hESCs

hESC 对造血分化的控制

• 批准号: 8379984
• 负责人: Jerome A. Zack
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8379984
• 关键词: Blood; Bone Marrow; Cell Therapy; Cells; Cellular biology; Clinical; Clinical Treatment; Coculture Techniques; Data; Databases; Development; Disease; Embryonic Development; Epigenetic Process; Erythroid; Gene Expression; Gene Expression Microarray Analysis; Gene Expression Regulation; Generations; Genes; Growth; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Heterogeneity; Human; Immune response; Immune system; Immunodeficient Mouse; Implant; In Vitro; Investigation; Knowledge; Laboratories; Link; Lymphoid; Lymphoid Cell; Methods; Modeling; Molecular; Monitor; Mus; Myelogenous; Organ; Process; Production; Replacement Therapy; Research; Resources; Signal Transduction; Solid; Staging; Stem Cell Development; Stress; Stromal Cells; Structure; Surface; System; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; base; cell type; gene therapy; human embryonic stem cell; human embryonic stem cell line; improved; in vitro Model; in vivo; method development; mouse model; novel; programs; reconstitution; self-renewal; stem cell differentiation; treatment strategy

Project 3. Control of Hematopoietic Differentiation by hESCs The theoretical ability of human embryonic stem cells (hESC) to differentiate into any cell type in the body opens the possibility of improved cell based therapies. The most common cell based therapeutic approach currently used is hematopoietic stem cell (HSC) transplantation. Thus the potential for adaptation of hESC to clinical use is especially true for diseases of the hematopoietic system. To date, certain hematopoietic lineages have been derived from hESC in vitro, however the process is quite inefficient. We have found that different hESC lines vary significantly in their ability to form hematopoietic colonies in vitro, suggesting epigenetic differences in control of gene expression between these lines. Recently our laboratory also demonstrated that human T cells can be generated from hESC using a combination of in vitro co-culture of hESC on bone marrow stromal cells or embryoid body cultures, followed by introduction of partially differentiated precursors into human thymic implants in immunodeficient mice. However multi-lineage hematopoiesis in vivo has not been established, nor has the ability of hESC-derived cells to mount effective anamnestic immune responses. Together with the Cores in this Program, we propose to optimize hematopoietic differentiation, stressing T-lineage development, using both in vitro and in vivo approaches. We will investigate epigenetic control of genes relevant to T cell development, and explore the ability to reconstitute human immune responses derived from hESC in chimeric mouse models. We propose the following specific aims: 1) Optimize in vitro methods for growth and expansion of hematopoietic progenitor cells derived from hESC; 2) Assess potential of hESC for T lymphoid development; 3) Determine the in vivo potential for multi-lineage hematopoiesis derived from hESC. Epigenetic data will be shared with Projects 1 and 2 to build a solid database regarding control of hESC differentiation, and we will utilize novel culture surfaces produced in Core B to optimize differentiation. Thus we will leverage the resources of this Program to improve our knowledge of how to utilize hESC to reconstitute the immune system. These studies could thus be important to set the stage for hESC-based therapeutics for a wide variety of hematopoietic disorders.

项目3。hESC控制造血分化的控制 人类胚胎干细胞（HESC）分化为体内任何细胞类型的理论能力 打开改善基于细胞的疗法的可能性。最常见的基于细胞的治疗方法 目前使用的是造血干细胞（HSC）移植。因此，hESC适应的潜力 对于造血系统的疾病，临床使用尤其如此。迄今为止，某些造血 谱系是从hESC中得出的，但是该过程效率很低。我们发现 不同的hESC线在体外形成造血菌落的能力上有显着差异，这表明 这些线之间对基因表达的控制的表观遗传差异。最近我们的实验室 证明可以使用hESC生成人类T细胞，并使用体外共培养的组合 hESC在骨髓基质细胞或胚胎体培养上，然后部分引入 分化为免疫缺陷小鼠中人胸腺植入物的前体。但是多部队 尚未建立造血体，也没有建立hESC衍生细胞有效的能力 吞噬免疫反应。与该程序中的核心一起，我们建议优化 造血分化，使用体外和体内方法都强调T-linege发育。 我们将研究与T细胞发育相关的基因的表观遗传控制，并探讨 在嵌合小鼠模型中衍生自HESC的人类免疫反应。我们建议 以下特定目的：1）优化造血祖细胞生长和扩展的体外方法 源自hESC的细胞； 2）评估hESC对T淋巴样发育的潜力； 3）确定体内 从hESC衍生的多种型造血的潜力。表观遗传数据将与项目共享1 和2建立有关控制hESC差异化的坚实数据库，我们将利用新文化 核心B中产生的表面以优化分化。因此，我们将利用该计划的资源 为了提高我们如何利用hESC重建免疫系统的知识。这些研究可以 因此，为基于HESC的各种造血疾病奠定阶段很重要。