Embryonic origin and self-renewal of B-1a cells

B-1a 细胞的胚胎起源和自我更新

• 批准号: 9294927
• 负责人: Momoko Yoshimoto
• 金额: $ 37.67万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294927
• 关键词: Adult; Antibodies; Atherosclerosis; B-Lymphocytes; Bacteria; Bacterial Infections; Biological Assay; Bone Marrow; Cell Count; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Clinical; Data; Development; Embryo; Encapsulated; Endothelial Cells; Fatty acid glycerol esters; Fetal Liver; Fetus; Frequencies; Goals; Greater sac of peritoneum; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Host Defense; Human; Human Development; Immune; Immunoglobulin M; Impairment; Innate Immune System; Investigation; Kidney; Knowledge; Life; Lymphoid; Maintenance; Mesentery; Methods; Molecular; Mus; Neonatal; Omentum; Organ; Outcome; PRC1 Protein; Pathway interactions; Patients; Peritoneal; Play; Polycomb; Process; Proteins; Reporting; Research; Role; Sepsis; Site; Source; Stem cell transplant; Stem cells; Systemic Lupus Erythematosus; T-Lymphocyte; Tamoxifen; Testing; Time; Translating; Transplantation; Virus Diseases; Yolk Sac; base; cell type; experimental study; fetal; gene repression; graft vs host disease; high risk; human subject; innovation; man; member; microbial; mouse model; peripheral blood; postnatal; prevent; progenitor; reconstitution; self-renewal; stem; tool

PROJECT SUMMARY/ABSTRACT B-1 cells are murine innate immune B cells that preferentially localize in the peritoneal cavity, secrete natural antibodies in a T cell independent manner, and play important roles in the first line of defense against bacterial or viral infections, sepsis, and atherosclerosis. Despite the importance of B-1 cells in host defense and homeostasis, their developmental origin is not clear. CD5+B-1a cells residing in the peritoneal cavity can be reconstituted by transplantation of fetal liver (FL) progenitors, but not by adult bone marrow (BM) hematopoietic stem cells (HSCs). Thus B-1a cells are considered to be of fetal origin and the mechanisms that maintain B-1a cells in adult life without being replenished by adult HSCs have yet to be elucidated. The overall goal of the project is to determine the contribution of HSC-independent embryonic B-1 progenitor cells into the adult peritoneal B-1a cells and define the mechanisms that maintain B-1a cells throughout adult life. We have reported the presence of B-1 progenitor cells originated from hemogenic endothelial cells (HECs) in the yolk sac (YS) in an HSC-deficient mouse model. Our recent preliminary data demonstrated that fetal liver HSCs poorly reconstituted B-1a cells upon transplantation. Thus, we hypothesize that peritoneal B- 1a cells are derived from HECs and are totally independent of HSCs contributions at any stage of development or adult life. In Aim 1, we will utilize a lineage tracing mouse model where one can mark HECs and their progeny at a specific embryonic time point before HSC emergence by tamoxifen induction and we will supplement this approach with HSC transplantation assays from fetus to neonatal and adult stages to prove there is no contribution of HSCs into the B-1a cell pool. In Aim2, we will interrogate the molecular mechanisms that maintain the self-replenishing ability of embryonic derived B-1a cells throughout life. Bmi1 is a polycomb group protein that is critical for self-renewal of HSCs. We now report that the self-replenishing capacity of Bmi1-/- and CD19Cre:Bmi1flox/flox B-1a cells is impaired, raising the hypothesis that Bmi1 plays an important role in B-1a cell self-renewal. Since Bmi1-/- mice displayed a significantly more severe reduction in B-1a cell number compared to CD19Cre:Bmi1flox/flox mice, we hypothesize that the B-1a cell microenvironment may be altered in Bmi1-/- mice. We will examine a niche for B-1 cells, the recently reported fat-associated lymphoid clusters (FALCs) in the omentum and mesentery, in Bmi1-/- mice. We will also pursue a downstream target of Bmi1 as playing a role in B-1a self-renewal. These experiments consider cell intrinsic and extrinsic roles of Bmi1 to define its critical role in B-1a cell maintenance and self-renewal. Our results will establish a new paradigm for understanding B-1 cell development and maintenance in mice and will provide new tools to translate to human investigation of B-1 like cells. 1

项目总结/摘要 B-1细胞是鼠先天免疫B细胞，其优先定位于腹膜腔中，分泌 天然抗体以不依赖于T细胞的方式存在，并在对抗T细胞的第一道防线中发挥重要作用。 细菌或病毒感染、败血症和动脉粥样硬化。尽管B-1细胞在宿主防御中的重要性 和体内平衡，它们的发育起源尚不清楚。驻留在腹膜腔中的CD 5 +B-1a细胞可以 通过移植胎肝（FL）祖细胞而不是通过成人骨髓（BM）重建 造血干细胞（HSC）。因此，B-1a细胞被认为是胎儿来源的， 维持B-1a细胞在成年期而不被成年HSC补充的方法还有待阐明。整体 该项目的目标是确定HSC非依赖性胚胎B-1祖细胞对造血干细胞的贡献。 成年腹膜B-1a细胞，并定义了在整个成年生活中维持B-1a细胞的机制。 我们已经报道了来源于造血内皮细胞的B-1祖细胞的存在 在HSC缺陷型小鼠模型中，在卵黄囊（YS）中的内皮细胞（HEC）。我们最近的初步数据表明， 胎肝HSC在移植后重建B-1a细胞较差。因此，我们假设腹膜B- 1a细胞来源于HEC，在任何发育阶段都完全不依赖HSC的贡献 或成人生活。在目标1中，我们将利用谱系追踪小鼠模型，其中可以标记HEC及其 在HSC出现之前的特定胚胎时间点通过他莫昔芬诱导子代，我们将 用从胎儿到新生儿和成人阶段的HSC移植试验补充该方法，以证明 HSC没有贡献到B-1a细胞库中。在Aim 2中，我们将询问 其维持胚胎来源的B-1a细胞在整个生命中的自我补充能力。Bmi 1是一种多梳型 这是一组对HSC自我更新至关重要的蛋白质。我们现在报告， Bmi 1-/-和CD 19 Cre：Bmi 1 flox/flox B-1a细胞受损，提出了Bmi 1在其中发挥重要作用的假设 在B-1a细胞自我更新中。由于Bmi 1-/-小鼠在B-1a细胞中显示出显著更严重的减少， 与CD 19 Cre：Bmi 1 flox/flox小鼠相比，我们假设B-1a细胞微环境可能是 在Bmi 1-/-小鼠中改变。我们将研究B-1细胞的小生境，这是最近报道的脂肪相关淋巴细胞。 在Bmi 1-/-小鼠中，网膜和肠系膜中的细胞簇（CMCs）。我们还将追求下游目标， Bmi 1在B-1a自我更新中起作用。这些实验考虑了细胞的内在和外在作用， Bmi 1，以确定其在B-1a细胞维持和自我更新中的关键作用。我们的研究结果将建立一个新的 为理解小鼠B-1细胞的发育和维持提供了新的工具， 转化为人类研究B-1样细胞。 1