Novel Agents for the Proliferation of Stem Cells

干细胞增殖的新型药物

• 批准号: 7608957
• 负责人: CYNTHIA C. BAMDAD
• 金额: $ 18.13万
• 依托单位: MINERVA BIOTECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608957
• 关键词: Affinity; Antibodies; Arts; BFU-E; Binding; Biological Assay; Bone Marrow; Brain; Cell Cycle; Cell-Free System; Cells; Code; Condition; Conditioned Culture Media; Development; Diabetes Mellitus; Dimerization; Dose; Epithelial; Evaluation; Fibroblast Growth Factor 2; Fluorouracil; Government; Growth; Growth Factor; Growth Factor Receptors; Heart failure; Hematopoietic; Human; Human body; In Vitro; Kidney; Kinetics; Lead; Length; Ligands; Malignant Neoplasms; Measures; Membrane; Methods; Modeling; Molecular; Monoclonal Antibodies; Mucin-1 Staining Method; Mus; Mutation; Myocardium; NME1 gene; Numbers; Organ; Persons; Pluripotent Stem Cells; Population; Proliferating; Property; Proteins; Protocols documentation; Public Health; Purpose; Range; Reagent; Recovery; Reporting; Retinal Diseases; Signal Transduction; Solid Neoplasm; Spinal Cord; Spinal cord injury; Staining method; Stains; Stem cells; Surface; Testing; Therapeutic; Therapeutic Intervention; Thinking; Tissues; Undifferentiated; United States National Institutes of Health; WA09 Cell Line; Withdrawal; brain tissue; cancer cell; cell growth; cell type; chemotherapy; desire; dimer; embryonic stem cell; growth promoting activity; human embryonic stem cell; in vivo; mutant; neoplastic cell; novel; pluripotency; progenitor; rapid growth; receptor; repaired; research study; response; stem cell therapy; therapeutic target; tool

DESCRIPTION (provided by applicant): Pluripotent (undifferentiated) stem cells possess the ability to become virtually any cell type in the human body and therefore, in principal, could be used to replace damaged tissues in organs that have traditionally been thought not to have a significant potential for functional self-repair such as heart muscle, spinal cord, brain tissue and kidney. However, to implement these therapies, one must have the ability to identify, isolate and proliferate populations of pluripotent stem cells. The first problem is that current methods for identifying pluripotent stem cells are insufficient. We have identified a new marker of pluripotency that discriminates between two different cell types within a population that current methods identify as being all "pluripotent". Secondly, it is difficult to culture embryonic stem cells (ESCs) without initiating differentiation. Growing ESCs under current state of the art protocols will yield only 50-75% undifferentiated colonies. This is in large part due to the fact that they are grown over a layer of "feeder" cells which secrete poorly understood factors, some of which promote the growth of undifferentiated stem cells and others that undoubtedly trigger differentiation. Factors secreted by neighboring cells influence how pluripotent stem cells differentiate. For example, pluripotent stem cells can be influenced to differentiate into a particular cell type by growing them over tissues of the desired cell type. What is needed is a cell-free system for growing ESCs in which only discrete, well-characterized agents are added to drive their growth. We have succeeded in growing ESCs in a cell-free system by adding a single agent that activates a newly identified growth factor receptor on the surface of ESCs - conditioned media from feeder cells was not added. The resultant population was 100% pluripotent and was signaled to differentiate by the withdrawal of our novel agent. This is a major step toward understanding the molecular drivers that maintain pluripotency as well as those that initiate differentiation and will enable stem cell therapies that are currently out of reach. Thus the isolation and propagation of pure pools of pluripotent stem cells will be critical for therapeutic applications of stem cell therapy for the repair of brain and spinal cord injuries, diabetes, cardiac failure, retinopathies and further will enable a whole range of therapeutic interventions that are currently not possible. PUBLIC HEALTH RELEVANCE: Pluripotent (undifferentiated) stem cells possess the ability to become virtually any cell type in the human body and therefore, in principal, could be used to replace damaged tissues in organs that have traditionally been thought not to have a significant potential for functional self-repair such as heart muscle, spinal cord, brain tissue and kidney. However, to implement these therapies, one must have the ability to identify, isolate and proliferate populations of pluripotent stem cells. We have succeeded in growing ESCs in a cell-free system by adding a single agent that activates a newly identified growth factor receptor on the surface of ESCs - conditioned media from feeder cells was not added.

描述（由申请人提供）：多能（未分化）干细胞具有成为人体内几乎任何细胞类型的能力，因此原则上可用于替代传统上被认为不具有功能性自我修复潜力的器官中的受损组织，例如心肌、脊髓、脑组织和肾脏。然而，为了实施这些疗法，人们必须具有识别、分离和增殖多能干细胞群的能力。第一个问题是目前鉴定多能干细胞的方法不足。我们已经确定了一种新的多能性标记，可以区分群体中两种不同的细胞类型，目前的方法将其识别为全“多能性”。其次，在不开始分化的情况下很难培养胚胎干细胞（ESC）。在当前最先进的方案下培养 ESC 将仅产生 50-75% 的未分化集落。这在很大程度上是由于它们生长在一层“饲养”细胞上，这些细胞分泌的因子知之甚少，其中一些因子促进未分化干细胞的生长，而另一些因子无疑会引发分化。邻近细胞分泌的因子影响多能干细胞的分化方式。例如，通过在所需细胞类型的组织上生长，可以影响多能干细胞分化成特定的细胞类型。我们需要的是一种用于生长 ESC 的无细胞系统，其中仅添加离散的、特征良好的试剂来驱动其生长。我们通过添加一种能够激活 ESC 表面新鉴定的生长因子受体的单一试剂，成功地在无细胞系统中培养 ESC - 未添加来自饲养细胞的条件培养基。由此产生的群体是 100% 多能的，并通过撤回我们的新药物发出分化信号。这是朝着了解维持多能性以及启动分化的分子驱动因素迈出的重要一步，并将使目前无法实现的干细胞疗法成为可能。因此，纯多能干细胞库的分离和增殖对于干细胞疗法修复脑和脊髓损伤、糖尿病、心力衰竭、视网膜病的治疗应用至关重要，并且进一步将使目前不可能的一系列治疗干预成为可能。公共健康相关性：多能（未分化）干细胞具有成为人体内几乎任何细胞类型的能力，因此原则上可用于替换传统上被认为不具有功能性自我修复潜力的器官中的受损组织，例如心肌、脊髓、脑组织和肾脏。然而，为了实施这些疗法，人们必须具有识别、分离和增殖多能干细胞群的能力。我们通过添加一种能够激活 ESC 表面新鉴定的生长因子受体的单一试剂，成功地在无细胞系统中培养 ESC - 未添加来自饲养细胞的条件培养基。