High resolution lineage tracing of developmental hematopoiesis

发育造血的高分辨率谱系追踪

• 批准号: 10585400
• 负责人: Fernando Camargo
• 金额: $ 77.75万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585400
• 关键词: Ablation; Adult; Age; Aging; Anatomy; Aorta; Arteries; Bar Codes; Biology; Birth; Blood; Blood Cells; Bone Marrow Transplantation; Cell Lineage; Cell Ontogeny; Cells; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Developmental Biology; Dissociation; Embryo; Endothelial Cells; Endothelium; Epigenetic Process; Event; Goals; Growth; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Specification; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; In Situ; In Vitro; Laboratories; Link; Mammals; Maps; Minority; Modeling; Molecular; Multipotent Stem Cells; Neonatal; Patients; Phenotype; Physiological; Population; Process; Production; Prognosis; Resolution; Site; Source; Specific qualifier value; Stress; System; Testing; Therapeutic; Time; Tissues; Transplantation; Work; Yolk Sac; blastomere structure; cell type; effective therapy; embryo cell; experimental study; improved; insight; multiple omics; population based; postnatal; premature; progenitor; recruit; stem cells; tool; young adult

Project Summary/Abstract: Investigating the origin of cell types is key to understanding basic processes in developmental biology and to enable in vitro production of cells and tissues for therapeutic benefit. While major advances in our understanding the ontogeny of hematopoietic cells have been made, significant technical limitations have precluded us from having a full picture of the lineage relationships of blood cells during development. For instance, the prevailing view in the field is that hematopoietic stem cells (HSCs) that emerge in the embryo are the cells responsible for lifelong blood production in the mammal. However, limited data exist that analyse the long-term fate of the earliest hematopoietic progenitors entirely in situ. Furthermore, the field still lacks a conclusive understanding of the true anatomical site of origin of the cells that will become the lifelong HSCs/progenitors in the adult. The Camargo and Hormoz laboratories have pioneered the use of in situ mammalian barcoding strategies to perform lineage tracing at the single cell level. Our proposal here aims to utilize these systems investigate the developmental origins of hematopoiesis. Our application is based on our identification of a population of non-transplantable embryonic multipotent progenitors (eMPPs) that contribute long-term to post-natal hematopoiesis. These findings imply that progenitor populations in addition to traditional HSCs have an active and substantial contribution to adult multilineage blood production. Our first goal in this application is to further characterize eMPPs molecularly and functionally. We will also explore the idea that functional differences in hematopoietic lineages can arise based on their eMPP or HSC ontogeny. Finally, we will extend the use of our barcoding approaches to broadly and unbiasedly characterize developmental waves of blood production and their exact site of origin. Our work has the potential to uncover basic mechanisms of blood development that could be useful for therapeutic manipulation.

项目摘要/摘要： 调查细胞类型的起源是理解发育生物学中的基本过程和 使细胞和组织的体外生产获得治疗益处。虽然我们理解的主要进步 已经制定了造血细胞的个体发育，严重的技术局限性使我们无法 在发育过程中充分了解血细胞的谱系关系。例如，盛行 在现场的观点是，出现在胚胎中的造血干细胞（HSC）是负责的细胞 哺乳动物中的终身血液产生。但是，存在有限的数据，可以分析最早的长期命运 造血祖细胞完全原位。此外，该领域仍然缺乏对真实的结论性理解 细胞的起源解剖部位将成为成年人终生的HSC/祖细胞。 Camargo Hormoz实验室已经开创了使用原位哺乳动物条形码策略来执行血统的使用 跟踪在单细胞水平。我们在这里的建议旨在利用这些系统调查发展 造血的起源。我们的应用是基于我们确定不可迁移的人群 胚胎多能祖细胞（EMPPS）长期对产后造血作用。 这些发现表明，除传统的HSC外，祖细胞具有活跃而实质性的 对成人多素血的产生的贡献。我们在此应用程序中的第一个目标是进一步表征 EMPPS分子和功能。我们还将探讨造血的功能差异的想法 谱系可能会根据其EMPP或HSC个体发育而产生。最后，我们将扩展条形码的使用 广泛和公正地表征了血液产生的发育浪潮及其确切的方法 原产地点。我们的工作有可能发现血液发育的基本机制可能有用 用于治疗性操纵。