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.人类胚胎干细胞对造血分化的控制 人类胚胎干细胞(HESC)分化为体内任何细胞类型的理论能力 开启了改进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的适应潜力 临床应用尤其适用于造血系统疾病。到目前为止，某些造血剂 人胚胎干细胞已经在体外获得了谱系，但这一过程的效率很低。我们发现， 不同的hESC株在体外形成造血祖细胞集落的能力有显著差异，提示 这些品系之间基因表达控制的表观遗传差异。最近我们实验室也 证明利用体外共培养的方法可以从hESC中产生人类T细胞 HESC在骨髓基质细胞或类胚体培养上的应用 将分化的前体细胞植入免疫缺陷小鼠的人胸腺。然而，多血统 体内的造血功能尚未建立，hESC来源的细胞也没有有效的装载能力。 记忆免疫反应。与本计划中的核心一起，我们建议优化 造血分化，强调T系的发展，使用体外和体内方法。 我们将研究与T细胞发育相关的基因的表观遗传控制，并探索 在嵌合小鼠模型中重建hESC来源的人类免疫反应。我们建议 具体目标如下：1)优化造血祖细胞体外生长扩增方法 HESC来源的细胞；2)评估hESC对T淋巴细胞发育的潜力；3)确定体内 人胚胎干细胞来源的多系造血潜能。表观遗传数据将与项目1共享 和2建立关于hESC分化控制的坚实数据库，我们将利用新的培养 在核心B中生产的表面，以优化差异化。因此，我们将利用该计划的资源 以提高我们对如何利用hESC重建免疫系统的了解。这些研究可能 因此，为基于hESC的多种造血疾病的治疗奠定基础是很重要的。