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: 10449115
• 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/10449115
• 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.

项目摘要/摘要 造血干细胞(HSCs)在一生中持续存在，以生成所有血细胞。微环境 利基对造血干细胞进行严格的调控。骨髓是成年造血干细胞驻留的主要器官。快速发展 已有关于骨髓HSC生态位的性质和机制的研究。有趣的是，HSCs 在发育和应激过程中改变组织和生态位。胎肝是主要的造血器官 在那里，HSCs迅速自我更新。在出生前后，肝脏失去支持HSC的活性，HSC外流到 在骨髓中播种。肝脏可以成为造血细胞，并支持骨髓外的造血干细胞 应激和某些血液病的造血(EMH)。然而，与骨髓相比，几乎没有 已知肝脏HSC在发育和应激状态下的生态位。我们的初步数据确定了星状 细胞作为体内胎肝HSC生态位的一个新的关键成分。此外，我们还确定了一个 转录因子LHX2，是星状细胞作为HSCs的利基细胞正常细胞命运所必需的 胎儿的肝脏。这项拟议研究的目标是利用我们对胎儿肝脏生态位的了解来 阐明LHX2在星状细胞发育过程中的作用。我们还将研究其性质和机制。 成年的EMH肝脏生态位。预计这些研究的结果不仅将提供关于如何 肝脏生态位调节HSCs，但也有可能识别介导产生 扩增供临床使用的造血干细胞的新利基。