Expansion of Cardiac and Hematopoietic Pregenitors by Wnt and Notch

Wnt 和 Notch 扩增心脏和造血祖细胞

• 批准号: 8462673
• 负责人: IRWIN D BERNSTEIN
• 金额: $ 115.15万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462673
• 关键词: Address; Adult; Affect; Behavioral; Biological Preservation; Cardiac; Cell Count; Cells; Chromatin; Clinical; Clinical Trials; Commit; DNA Methylation; Derivation procedure; Development; Embryo; Endothelium; Engineering; Ensure; Epigenetic Process; Generations; Genes; Goals; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Link; Malignant - descriptor; Methods; Modeling; Moon; Mus; Mutation; Notch and Wnt Signaling Pathway; Pathway interactions; Pear; Physiological; Population; Role; Signal Transduction; Staging; Stem cells; Stimulus; Testing; Therapeutic; Therapeutic Uses; Therapy Clinical Trials; Time; Umbilical Cord Blood; cell type; embryonic stem cell; human embryonic stem cell; in vivo; induced pluripotent stem cell; method development; mutant; notch protein; progenitor; self-renewal; stem; stem cell fate specification; stem cell population

DESCRIPTION (provided by applicant): The generation of desired cell types for therapeutic purposes is becoming a reality with the development of methods for deriving such cells from embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), as well as from isolated adult stem/progenitor cells or differentiated cells that are directly "reprogrammed" into lineage-specific stem/progenitor cells. Realizing this goal, however, will require methods for deriving therapeutically useful numbers of cells that avoid inducing permanent genetic alterations, and ensure the behavioral fidelity of derived lineage-committed stem/progenitor cells. To address this issue, we propose to test our hypotheses that pathways regulating normal development can be manipulated to direct differentiation and expansion of populations of cell types that reflect normal developmental states. As a model for this approach, we focus on the Notch and Wnt pathways and the well-characterized hematopoietic system to generate hematopoietic stem cells (HSC). The feasibility of expanding therapeutically useful stem/progenitor cells is demonstrated by our expansion of cord blood-derived stem/progenitor cells and by our successful application of these cells in a clinical setting. Specifically, we will examine the requirement for and timing of Notch and Wnt signaling in generating the first HSCs in the embryo, to guide our efforts to produce these cells ex vivo. We will generate ES- and iPS-derived HSC by enhancing differentiation towards hemogenic endothelial precursors of definitive hematopoietic stem/progenitor cells, and by promoting selfrenewal of these multipotent stem/progenitor populations (Project 1). To assess the therapeutic usefulness of human ES- and iPS-derived stem/progenitor cells, we will determine their preservation of the transcriptional, chromatin and DNA methylation and functional landscapes (Project 2). These studies will interface with those described in the collaborative linked application on the role of Wnt and Notch in expansion and proper differentiation of cardiac stem cells.

描述（由申请人提供）：