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

基本信息

批准号：
10666495
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
项目类别：
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/10666495
关键词：
Adult Aging Biological Assay Birth Blood Blood Cells Blood Vessels 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 Source Stem Cell Factor Stress Supporting Cell System Testing Tissues Vascular blood supply candidate identification 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 stem cell function stem cell migration transcription factor

项目摘要

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) 终生持续存在以产生所有血细胞。微环境利基对 HSC 具有严格的调节作用。骨髓是成体造血干细胞驻留的主要器官。快速进步关于骨髓 HSC 生态位的性质和机制已经有了一些进展。有趣的是，HSC 在发育和应激过程中改变组织和生态位。胎儿肝脏是主要的造血器官 HSC 能够快速自我更新。出生前后，肝脏失去 HSC 支持活性，HSC 会逃逸至播种骨髓。肝脏可以造血并支持髓外的造血干细胞应激和某些血液系统疾病中的造血作用（EMH）。然而，与骨髓相比，几乎没有众所周知，肝脏 HSC 在发育和应激过程中的生态位。我们的初步数据确定了恒星细胞作为体内胎儿肝脏 HSC 生态位的新关键成分。此外，我们还确定了一个转录因子 Lhx2，是星状细胞作为 HSC 的微环境细胞的正确细胞命运所必需的胎儿肝脏。拟议研究的目标是利用我们对胎儿肝脏生态位的了解阐明 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人 EMH 肝脏生态位。这些研究的结果预计不仅会提供关于如何肝脏生态位调节 HSC，但也有可能确定介导 HSC 生成的机制扩大 HSC 供临床使用的新利基。