Hematopoiesis from Normal and Patient-Derived Induced Pluripotent Stem Cells

描述(由申请人提供)：该项目涉及NHLBI RC2 GO应用程序，标题为“通过对人类胚胎和诱导的多能干细胞进行重新编程而获得的分化的心、肺和血细胞的特征。”通过对人类体细胞重新编程来产生诱导多能干细胞(IPSCs)的新兴技术有望给生物医学研究和临床医学带来革命性的变化。通过体外培养方法，IPSCs可以分化为来自所有三个胚层的多种细胞类型。这增加了患者来源的IPSCs可以用来创造相关组织用于研究许多人类疾病的可能性。此外，IPSCs可能会为制造用于输血和再生治疗的可移植细胞提供起始材料。然而，该领域还处于初级阶段，必须解决许多核心问题，才能实现这些令人兴奋的长期前景。这项建议旨在促进IPSCs在正常和病理性造血研究中的应用。多位在造血学、胚胎干细胞/IPSC生物学、染色质生物学、临床血液学、生物信息学、细胞库和生物伦理/监管事务方面拥有广泛专长领域的研究人员将共同努力，探讨下列全球性问题：1)不同正常IPSC克隆之间造血发育潜力可能存在差异的机制；2)IPSC来源的造血前体在细胞表型、基因表达和表观遗传学特征方面与正常造血前体细胞的相似程度；3)体外操作患者来源的IPSC能否重塑造血疾病表型。我们将使用新的方法进行这些研究，以创造和培养IPSC，并使用最先进的工具来分析和操纵它们的常驻基因组。对这些问题的研究将作为一个框架，在其中开发一个便捷的基础设施，我们大型儿科机构的研究人员可以在其中创建、分析、存储和分发来自任何感兴趣的患者的IPSC。如果成功，这项工作将有助于加快IPSCs在人类疾病研究和治疗中的实际应用。这项工作将设在费城儿童医院，分包给宾夕法尼亚州立大学(宾夕法尼亚州州立学院)和科里尔医学研究所(新泽西州卡姆登)。该项目将创造6个新的就业机会，从而刺激美国东北部三个不同地区的经济。 公共卫生相关性：更好地了解患者来源的诱导多能干细胞(IPSCs)产生的血液将增强我们对血液疾病的理解，并产生新的治疗方法。此外，这项工作可以为研究许多正常组织及其相关疾病的起源创造新的一般范式。

DESCRIPTION (provided by applicant): This project addresses the NHLBI RC2 GO application entitled "Characterizing Differentiated Heart, Lung, and Blood Cells Derived by Reprogramming Human Embryonic and Induced Pluripotent Stem Cells." Emerging technologies to generate induced pluripotent stem cells (iPSCs) by reprogramming human somatic cells promises to revolutionize biomedical research and clinical medicine. Through in vitro culture methods, iPSCs can be differentiated into numerous cells types derived from all three germ layers. This raises the possibility that patient-derived iPSCs can be used to create relevant tissues for the study of many human disorders. In addition, iPSCs may provide starting material to manufacture transplantable cells for transfusion and regenerative therapies. However, the field is in its infancy and many core questions must be solved in order to realize these exciting long-term prospects. This proposal seeks to advance the use of iPSCs for the study of normal and pathological hematopoiesis. Multiple investigators with broad areas of expertise in hematopoiesis, embryonic stem cell/iPSC biology, chromatin biology, clinical hematology, bioinformatics, cell banking and bioethics/regulatory affairs will work together to pursue the following global issues 1) Mechanisms by which hematopoietic developmental potential might vary between different normal iPSC clones; 2) The extent to which iPSC-derived hematopoietic precursors resemble normal ones with respect to cellular phenotypes, gene expression and epigenetic signatures; 3) Whether hematopoietic disease phenotypes can be recapitulated by in vitro manipulation of patient-derived iPSCs. We will execute these studies using novel methods to create and culture iPSCs and state-of-the art tools to analyze and manipulate their resident genomes. Pursuit of these problems will serve as a framework in which to develop a facile infrastructure where investigators at our large pediatric institution can create, analyze, bank and distribute iPSCs from any patient of interest. If successful, this work will help to accelerate practical applications of iPSCs for the study and treatment of human diseases. This work will be based at Children's Hospital of Philadelphia with subcontracts to The Pennsylvania State University (State College, PA) and The Coriell Institute for Medical Research (Camden, NJ). The project will create 6 new jobs, thereby stimulating the economy in three different regions of the Northeastern United States. PUBLIC HEALTH RELEVANCE: Efforts to better understand blood production from patient-derived induced pluripotent stem cells (iPSCs) will enhance our understanding of blood disorders and generate new therapeutic approaches. Additionally, this work could create new general paradigms for studying the genesis of many normal tissues and their associated diseases.