Biological Insights into Dynamics of Stem Cell Differentiation and Misbehavior

描述(申请人提供)：人类胚胎干细胞(HESCs)是来源于囊胚期胚胎内细胞团的多能细胞。它们对现代生物学和再生医学的重要性源于两个独特的特征，这两个特征使它们有别于迄今发现的所有其他器官特异性干细胞。首先，hESCs可以作为未分化细胞的纯群体在培养的较长时间内保持和扩增。其次，hESCs可以分化为体内的每一种细胞类型，包括神经细胞、心脏细胞、肝脏细胞和内皮细胞。然而，使用hESCs最具破坏性的风险之一仍然是细胞行为不当的可能性(即形成畸胎瘤)。因此，如果要实现这些细胞的临床潜能，就必须了解hESC在体外和体内分化的生物学过程。R21方案是一种系统的方法来研究这一问题，这是目前干细胞研究中一个未得到充分解决的问题。在目标1中，我们将监测活体动物中hESC不当行为的动态。在目标2中，我们将研究人胚胎干细胞向内皮细胞分化的过程。总而言之，我们相信，从这项提案中收集的数据将为未来基于hESC的治疗的安全临床翻译提供所需的重要信息。项目简介：人类胚胎干细胞(HESCs)具有自我更新和多谱系分化的独特能力。这为在基础研究水平上了解胚胎发育和在临床水平上应用基于hESC的再生医学开辟了令人兴奋的机会。然而，这些细胞在体内的行为或不当行为的基本生物学仍不清楚。特别是，了解hESCs是如何分化成特定的细胞系的，而不是其他细胞系，对于利用它们的潜在临床价值至关重要。在这项提案中，我们将整合我们在分子成像、基因组学和蛋白质组学方面的专业知识，使用联邦批准的两个hESC系(H1和H9)来回答这些问题。

DESCRIPTION (provided by applicant): Human embryonic stem cells (hESCs) are pluripotent cells derived from the inner cell mass of blastocyst-stage embryos. Their importance to modern biology and regenerative medicine derives from two unique characteristics that distinguish them from all other organ-specific stem cells identified so far. First, hESCs can be maintained and expanded as pure population of undifferentiated cells for extended periods of time in culture. Second, hESCs can differentiate into every cell type in the body, including neuronal, cardiac, hepatic, and endothelial cells. However, one of the most devastating risks of using hESCs remains the possibility of cellular misbehavior (i.e., teratoma formation). Thus, understanding the biological process of hESC differentiation in vitro and in vivo is a must if the clinical potential of these cells is to be realized. This R21 proposal is a systemic approach to study this problem, which is an under-addressed issue in stem cell research at present. In Aim 1, we will monitor the dynamics of hESC misbehavior in living animals. In Aim 2, we will investigate the differentiation process of hESCs into endothelial cells. Collectively, we believe data gathered from this proposal will provide vital information needed for safe clinical translation of hESC-based therapy in the future. PROJECT NARRATIVE: Human embryonic stem cells (hESCs) have the unique ability to undergo both self-renewal and multi- lineage differentiation. This opens up exciting opportunities for understanding embryonic development on a basic research level and for application of hESC-based regenerative medicine on a clinical level. However, the fundamental biology of how these cells behave or misbehave in vivo still remains unknown. In particular, understanding how hESCs differentiate into specific cell lineages versus others will be critically important for harnessing their potential clinical values. In this proposal, we will integrate our expertise in molecular imaging, genomics, and proteomics to answer these questions using two federally approved hESC lines (H1 and H9).