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： 研究细胞类型的起源是理解发育生物学基本过程和 能够在体外生产细胞和组织以获得治疗效果。虽然我们的理解取得了重大进展 造血细胞的个体发育已经完成，但重大的技术限制使我们无法 全面了解发育过程中血细胞的谱系关系。例如，目前流行的 该领域的观点是，胚胎中出现的造血干细胞（HSC）是负责 哺乳动物的终生血液生产。然而，分析最早的长期命运的数据有限。 造血祖细胞完全在原位。此外，该领域仍然缺乏对真实情况的结论性理解。 将成为成人终生 HSC/祖细胞的细胞的解剖起源位点。卡马戈 和霍尔木兹实验室率先使用原位哺乳动物条形码策略来进行谱系分析 在单细胞水平上进行追踪。我们的建议旨在利用这些系统来研究发育 造血的起源。我们的申请基于我们对不可移植群体的识别 胚胎多能祖细胞（eMPP）长期促进产后造血。 这些发现表明，除了传统的 HSC 之外，祖细胞群还具有活跃且大量的活性。 对成人多谱系血液生产的贡献。我们在此应用中的首要目标是进一步表征 eMPP 的分子和功能。我们还将探讨造血功能差异的观点 谱系可以基于其 eMPP 或 HSC 个体发育而产生。最后，我们将扩展条形码的使用 广泛且公正地描述血液产生的发育波及其确切特征的方法 原产地。我们的工作有可能揭示血液发育的基本机制，这可能是有用的 用于治疗操作。