The Production of Adult Red Blood Cells from Human Embryonic Stem Cells

从人胚胎干细胞产生成体红细胞

基本信息

批准号：
7990419
负责人：
Lisa Ann Marie Sarran
金额：
$ 4.18万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-02 至 2015-02-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990419
关键词：
Adult Animals Apoptosis CASP8 gene Cells Dependence Development Embryo Endothelium Erythrocytes Failure Generic Drugs Genetic Recombination Globin Goals Gonadal structure Health Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Hemoglobin Human In Vitro Lead Mediating Medical Mesoderm Cell Methods Mission Mus National Heart, Lung, and Blood Institute Patients Phenotype Procedures Production Protocols documentation Public Health RNA Interference Research Research Personnel Serum Signal Transduction Signaling Molecule Source System Tacrolimus Binding Proteins Technology Testing Therapeutic Tissues Transgenes Transplantation United States National Institutes of Health cell type embryonic stem cell fetal human embryonic stem cell in vivo promoter stem cell differentiation stem cell niche transcription factor

项目摘要

DESCRIPTION (provided by applicant): We propose to develop a method to differentiate human Embryonic stem cells into hematopoietic stem cells that can be transplanted in adults and differentiated in vitro into adult red blood cells (RBCs). To achieve this goal we will attempt to recapitulate the stem cell niches in which HSC normally develop, using chemically defined conditions, combined with elimination of unwanted signals in the culture produced by spontaneously differentiating cells in the culture. Aim 1 A: To develop a procedure to produce adult hematopoietic cells from human ES cells by blocking the differentiation of non-mesodermal cells by RNAi against transcription factors, and by adding a sequence of chemically defined developmentally appropriate signals. Aim 1 B: To attempt to recapitulate in vitro the essential signals of the AGM niche in which HSCs normally develop in vivo. Aim 2: To create a universal inducible system to negatively select for cells that do not express a specific promoter by using an inducible FKBP-caspase-8 gene that can induce apoptosis upon addition of a dimerizer. Combined with tissue specific cre-mediated recombination, this system will allow for the elimination of unwanted cells in differentiating hESCs culture system. The scope of this project is very relevant to the mission of the NIH National Heart Lung and Blood Institute (NHLBI) because it is related to the treatment of blood diseases. PUBLIC HEALTH RELEVANCE: This research is very relevant to public health because the ultimate medical goal is to create patient specific and generic hematopoietic stem cells that can be differentiated into cell types that can be used to cure some blood diseases.

描述（由申请人提供）：我们建议开发一种将人类胚胎干细胞分化为造血干细胞的方法，该方法可以移植到成人体内并在体外分化为成人红细胞（RBC）。为了实现这一目标，我们将尝试使用化学定义的条件，结合消除培养物中自发分化细胞产生的不需要的信号，来重现 HSC 正常发育的干细胞生态位。目标 1 A：开发一种方法，通过针对转录因子的 RNAi 阻断非中胚层细胞的分化，并添加一系列化学定义的发育适当信号，从而从人类 ES 细胞中产生成体造血细胞。目标 1 B：尝试在体外重现 HSC 在体内正常发育的 AGM 生态位的基本信号。目标 2：创建一个通用诱导系统，通过使用可在添加二聚体后诱导细胞凋亡的诱导型 FKBP-caspase-8 基因来阴性选择不表达特定启动子的细胞。与组织特异性 cre 介导的重组相结合，该系统将允许消除分化 hESC 培养系统中不需要的细胞。该项目的范围与 NIH 国家心肺和血液研究所 (NHLBI) 的使命非常相关，因为它与血液疾病的治疗有关。公共健康相关性：这项研究与公共健康非常相关，因为最终的医学目标是创造患者特异性和通用的造血干细胞，这些干细胞可以分化成可用于治疗某些血液疾病的细胞类型。