Lineage-specific reprogramming to blood with a transcription factor cocktail

使用转录因子混合物对血液进行谱系特异性重编程

• 批准号: 7811558
• 负责人: Michael Kyba
• 金额: $ 35.43万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811558
• 关键词: Address; Area; Binding; Biological Assay; Blood; Bone Marrow; Bone Marrow Transplantation; Cells; Chromatin; Doxycycline; ES Cell Line; Fibroblasts; Flow Cytometry; Genetic; Genomics; Germ Lines; Hematopoietic; Hematopoietic stem cells; Hereditary Disease; Human; Immune Tolerance; In Vitro; Injection of therapeutic agent; Isogenic transplantation; LMO2 gene; Mesenchymal Stem Cells; Mesoderm; Mesoderm Cell; Methodology; Methods; Mus; Muscle satellite cell; Myoblasts; Neonatal; Organ Transplantation; Patients; Pattern; Population; Regenerative Medicine; Reporter; Series; Source; Specific qualifier value; Stem cells; Subfamily lentivirinae; T-cell acute lymphocytic leukemia 1 protein; Technology; Testing; Therapeutic; Transcript; Transplantation; Undifferentiated; Work; blastocyst; cell type; embryonic stem cell; human embryonic stem cell; monolayer; nerve stem cell; novel; penis foreskin; progenitor; public health relevance; research study; transcription factor; transdifferentiation; vector

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (11) Regenerative Medicine and specific Challenge Topic, 11-DK-105: Transdifferentiation or directed reprogramming of one cell type to another. In work to understand how blood is patterned in early mesoderm, we have discovered that a cocktail of transcription factors interacts synergistically to cause cells that do not have the potential to become blood to convert to blood at high efficiency. When coexpressed during monolayer differentiation of ES cells, conditions under which no blood is ever made, this cocktail drives approximately 85% of total cells into the hematopoietic lineage within 4 days of induction. This efficiency of differentiation is unprecedented, and several lines of evidence indicate that it is due to reprogramming the fates of cells that were specified into other lineages. We propose to explore this lineage-specific reprogramming mechanistically with the objective of developing the technology to reprogram differentiated (or undifferentiated) cells of other lineages into repopulating hematopoietic stem cells useful for therapy. PUBLIC HEALTH RELEVANCE: We propose exploratory experiments to develop a method of reprogramming cells of other lineages to the blood lineage, with the objective of finding alternate sources of hematopoietic stem cells for bone marrow transplantation. If successful, direct reprogramming to blood-forming stem cells would enable immune tolerance for organ transplantation, genetic correction and syngeneic transplantation for genetic diseases of the blood, and expand the donor pool for patients in need of bone marrow transplantation.

描述（由申请人提供）：此申请涉及广泛的挑战领域（11）再生医学和特定挑战主题，11-DK-105：转分解或将一种单元格的重新编程到另一种细胞类型。在了解早期中胚层中血液图案的工作中，我们发现转录因子的鸡尾酒具有协同作用，从而引起细胞，这些细胞没有潜力成为血液以高效率转化为血液的细胞。当在ES细胞的单层分化过程中共表达时，在没有血液的情况下，该鸡尾酒在诱导后的4天内将约85％的总细胞驱动到造血谱系中。这种分化的效率是前所未有的，几条证据表明，这是由于对细胞的命运进行重编程，这些细胞的命运被指定为其他谱系。我们建议从机理上探索这种谱系特异性的重编程，目的是开发该技术以将其他谱系的分化（或未分化的）细胞重新培养为可重现的造血干细胞，可用于治疗。 公共卫生相关性：我们提出探索性实验，以开发一种将其他谱系细胞重编程为血统的方法，目的是寻找造血干细胞的替代来源以进行骨髓移植。如果成功，直接重新编程对血液形成的干细胞可以使身体移植，遗传矫正和血液遗传疾病的合成性移植能够免疫耐受性，并扩大需要骨髓移植的患者的供体库。