Control of Hematopoietic Differentiation by hESCs

项目3。通过hESC控制造血分化 人类胚胎干细胞（hESC）在体内分化为任何细胞类型的理论能力 开启了改良细胞疗法的可能性。最常见的细胞治疗方法 目前使用的是造血干细胞（HSC）移植。因此，hESC的适应潜力 对于造血系统疾病尤其如此。到目前为止，某些造血 已经在体外从hESC衍生出谱系，然而该过程是相当低效的。我们发现 不同的hESC系在体外形成造血集落的能力有显著差异，这表明 这些品系之间基因表达控制的表观遗传差异。最近，我们的实验室也 证明了人T细胞可以从hESC产生，使用体外共培养的组合， hESC在骨髓基质细胞或胚状体培养物上，随后引入部分 在免疫缺陷小鼠中分化前体到人胸腺植入物中。然而， 体内造血尚未建立，hESC衍生的细胞也没有能力有效地增加造血干细胞的数量。 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-谱系发育，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T细胞的能力， 在嵌合小鼠模型中重建源自hESC的人免疫应答。我们建议 具体目标如下：1）优化造血祖细胞体外生长和扩增的方法 hESC来源的细胞; 2）评估hESC用于T淋巴发育的潜力; 3）确定hESC的体内T淋巴细胞分化。 来源于hESC的多谱系造血的潜力。表观遗传学数据将与项目1共享 和2建立一个关于控制hESC分化的可靠数据库，我们将利用新的培养物， 核心B中产生的表面以优化分化。因此，我们将充分利用该计划的资源， 以提高我们对如何利用hESC重建免疫系统的认识。这些研究可以 因此，为基于hESC的治疗多种造血系统疾病奠定基础是重要的。

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.