Understanding the role of stellate cells in the liver hematopoietic stem cell niche

了解星状细胞在肝脏造血干细胞生态位中的作用

• 批准号: 10034524
• 负责人: Lei Ding
• 金额: $ 56.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10034524
• 关键词: Adult; Aging; Biological Assay; Birth; Blood; Blood Cells; Bone Marrow; Cell Maintenance; Cells; Cellular biology; Clinic; Clinical; Data; Defect; Development; Endothelial Cells; Environment; Extramedullary Hematopoiesis; Fetal Development; Fetal Liver; Foundations; Generations; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic stem cells; Hepatocyte; Knock-in Mouse; Knowledge; Life; Liver; Malignant Neoplasms; Mediating; Methods; Molecular Biology; Mus; Natural regeneration; Nature; Organ; Play; Research; Role; Seeds; Source; Stem Cell Factor; Stress; Supporting Cell; System; Testing; Tissues; Vascular blood supply; base; bone; cell type; cytokine; experimental study; fetal; hematopoietic stem cell expansion; hematopoietic stem cell niche; hematopoietic stem cell self-renewal; improved; in vivo; insight; novel; nuclease; self-renewal; single-cell RNA sequencing; stellate cell; transcription factor

Project summary/Abstract Hematopoietic stem cells (HSCs) persist throughout life to generate all blood cells. The microenvironmental niche critically regulates HSCs. The bone marrow is the major organ where adult HSCs reside. Rapid progress has been made regarding the nature and mechanisms of the bone marrow HSC niche. Interestingly, HSCs change tissues and niches during development and in stress. The fetal liver is the major hematopoietic organ where HSCs self-renewal rapidly. Around birth, the liver loses HSC-supporting activity and HSCs egress to seed the bone marrow. The liver can become hematopoietic and support HSCs in extramedullary hematopoiesis (EMH) in stress and some hematologic diseases. However, in contrast to the bone marrow, little is known about the liver HSC niche during development and in stress. Our preliminary data identified stellate cells as a novel key component of the fetal liver HSC niche in vivo. In addition, we have identified a transcriptional factor, Lhx2, that is required for the proper cell fate of stellate cells as the niche cell for HSCs in the fetal liver. The goal of the proposed research is to leverage our knowledge of the fetal liver niche to elucidate the role of Lhx2 in stellate cells during development. We will also study the nature and mechanisms of the adult EMH liver niche. The results of these studies are expected to not only provide new insights on how the liver niche regulates HSCs, but also have the potential to identify mechanisms mediating the generation of new niches to amplify HSCs for clinic use.

项目概要/摘要 造血干细胞（HSC）在整个生命过程中持续存在，以产生所有的血细胞。微环境 niche关键地调节HSC。骨髓是成体造血干细胞的主要器官。迅速进展 关于骨髓造血干细胞生态位的性质和机制，有趣的是，HSC 在发育和压力下改变组织和生态位。胎肝是主要的造血器官 HSC自我更新迅速。在出生前后，肝脏失去了HSC支持活性，HSC排出， 植入骨髓肝脏可以成为造血和支持造血干细胞在髓外 造血（EMH）在应激和某些血液病。然而，与骨髓相比， 已知在发育和应激期间肝脏HSC的生态位。我们的初步数据显示 细胞作为一种新的关键组成部分的胎肝HSC生态位在体内。此外，我们还发现了一个 转录因子Lhx 2，这是所需的适当的细胞命运的星状细胞作为小生境细胞的HSC， 胎儿肝脏这项研究的目的是利用我们对胎儿肝脏生态位的了解， 阐明Lhx 2在星状细胞发育过程中的作用。我们还将研究 成人EMH肝脏生态位的一部分。预计这些研究的结果不仅将提供有关如何实现这一目标的新见解， 肝脏小生境调节HSC，但也有可能确定介导HSC产生的机制。 为临床扩增HSC提供了新的利基。