The developmental pathway of fetal-derived B cells

胎儿来源的 B 细胞的发育途径

基本信息

批准号：
10735381
负责人：
Nichol Elizabeth Holodick
金额：
$ 7万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10735381
关键词：
Acute Address Adult Animals Antibodies Aorta Autoimmune Autoimmunity B-Cell Acute Lymphoblastic Leukemia B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Bar Codes Biological Blood Blood Cells Bone Marrow Bone Marrow Transplantation Cell Lineage Cell secretion Cells Cellular biology Cessation of life Complication Data Development Developmental Process Disease Embryo Embryonic Development Endothelial Cells Fetal Liver Fetus Frequencies Functional disorder Goals Gonadal structure Hematological Disease Hematology Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Immune Immune System Diseases Immune system Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin M Immunologic Deficiency Syndromes Immunology In Vitro Infection Intestines Invaded Knowledge Label Life Lymphocyte Lymphocyte Depletion Lymphoid Lymphoid Cell Lymphopoiesis Maps Mature B-Lymphocyte Mesonephric structure Microglia Modeling Mus Neonatal Pathology Pathway interactions Peritoneal Phase Play Population Pregnancy Production Recovery Reporting Research Role Sorting Spleen Streptococcus pneumoniae Technology Therapeutic Tissues Transplant Recipients Transplantation Trees Vaccination Visualization Yolk Sac adaptive immunity base blastomere structure cytokine embryo cell endothelial stem cell fetal hemogenic endothelium improved in vivo leukemia/lymphoma lymphoid organ mast cell microbial mouse model perinatal period postnatal progenitor response segregation stem cells theories transplantation therapy γδ T cells

项目摘要

Abstract Stem cell theory states that all the blood cells are derived from hematopoietic stem cells (HSCs) and is a central concept of hematology and immunology. Bone marrow transplant therapy for blood disorders is rooted in the concept that donor HSCs can replace all blood cells in the recipient's body. However, recent research has challenged the stem cell theory by showing that some tissue-resident immune cells develop from endothelial cells (EC) of the embryo in an HSC-independent manner and these immune cells may not be replaced by HSCs. Furthermore, it has been reported that a significant percentage of conventional B cells (B-2 cells) also originate from fetal EC progenitors in the embryo and persist into old mice. These striking results highlight a huge knowledge gap in the hematology and immunology fields because HSC-independent B-2 cell development has yet to be recognized. Since B cells play important roles in protecting against infections and in the pathology of autoimmune and other diseases, it is critically important to understand the developmental pathways of HSC- independent B-cells and their functions compared to HSC-derived counterparts. However, it is challenging to clarify the origins of these B-cells since there are multiple waves of hematopoiesis from ECs in the embryo, in which HSCs and HSC-independent blood progenitors seem to be produced simultaneously. Our preliminary data and other studies suggest that there are at least three waves of B-cell development; 1) innate-immune B-1 cell development, 2) common progenitors for innate B-1 and conventional B-2 cells, and 3) B-2 dominant progenitors derived from HSCs. Our objective is to determine the functional differences of B-cells based on their origins and to establish a revised B-cell development map from embryo to adult, using combinations of various lineage tracing and in vivo barcoding mouse models. To pursue these goals, Aim 1 will utilize HSC-labeling mice (100% labeling of HSCs is achieved) and the HSC-derived lymphoid cell depletion model so that HSC-independent and dependent B-cell subsets will be separated. Then, these HSC-independent and dependent B-cell subsets will be sorted and examined for 1) antibody and cytokine secretion, class switching upon in vitro stimulation, and their IgM repertoire, 2) in vivo repsonse to S. pneumoniae infection, and 3) response to pneumococcal vaccination. In Aim 2, preliminary data identified the earliest innate-immune restricted B-progenitors in the early fetal liver. Also, scRNA-sequencing of the neonatal spleen revealed three separate B-progenitor clusters, supporting our hypothesis. Thus, the EC-lineage tracing mouse model that can mark HSC-independent blood progenitors will be combined with in vivo barcoding, which will enable visualization of the clonal relationships between HSCs and fetal- and HSC-derived B-progenitors. The results obtained from this proposal will revise the current paradigm of B-cell development and will be utilized to understand pathology not previously recognized in the absence of recognizing the existance of various fetal-derived B cell subsets.

抽象的干细胞理论指出，所有的血细胞均源自造血干细胞（HSC），是造血干细胞的中枢。血液学和免疫学的概念。骨髓移植治疗血液疾病的根源在于供体 HSC 可以替代受体体内所有血细胞的概念。然而，最近的研究发现通过证明一些组织驻留免疫细胞从内皮细胞发育而来，对干细胞理论提出了挑战胚胎细胞（EC）以不依赖于 HSC 的方式存在，并且这些免疫细胞可能不会被 HSC 取代。此外，据报道，很大比例的传统 B 细胞（B-2 细胞）也起源于来自胚胎中的胎儿 EC 祖细胞并持续存在于老年小鼠中。这些惊人的结果突显了巨大的由于不依赖 HSC 的 B-2 细胞发育，血液学和免疫学领域的知识差距尚未被认可。由于 B 细胞在防止感染和病理学中发挥着重要作用自身免疫性疾病和其他疾病中，了解 HSC 的发育途径至关重要与 HSC 衍生的对应物相比，独立的 B 细胞及其功能。然而，这具有挑战性澄清这些 B 细胞的起源，因为胚胎中的 EC 存在多次造血波， HSC 和不依赖 HSC 的血液祖细胞似乎是同时产生的。我们的初步数据其他研究表明，B 细胞的发育至少经历了三个阶段； 1) 先天免疫B-1细胞发育，2) 先天 B-1 和传统 B-2 细胞的共同祖细胞，以及 3) B-2 显性祖细胞源自 HSC。我们的目标是根据 B 细胞的起源和功能确定其功能差异使用不同谱系的组合建立修订后的从胚胎到成体的 B 细胞发育图追踪和体内条形码小鼠模型。为了实现这些目标，目标 1 将利用 HSC 标记小鼠（100% 实现了 HSC 的标记）和 HSC 衍生的淋巴细胞耗竭模型，以便 HSC 独立且依赖的 B 细胞亚群将被分离。然后，这些 HSC 独立和依赖的 B 细胞亚群将进行分类和检查 1) 抗体和细胞因子的分泌、体外刺激时的类别转换，以及他们的 IgM 库，2) 对肺炎链球菌感染的体内反应，以及 3) 对肺炎球菌的反应疫苗接种。在目标 2 中，初步数据确定了早期最早的先天免疫限制性 B 祖细胞。胎儿肝脏。此外，新生儿脾脏的 scRNA 测序揭示了三个独立的 B 祖细胞簇，支持我们的假设。因此，可以标记 HSC 独立血液的 EC 谱系追踪小鼠模型祖细胞将与体内条形码相结合，这将使克隆关系可视化 HSC 与胎儿和 HSC 衍生的 B 祖细胞之间的关系。该提案获得的结果将修改 B 细胞发育的当前范例，将用于了解以前未认识到的病理学在没有认识到各种胎儿来源的 B 细胞亚群的存在的情况下。