Stem cell origins of human fetal/neonatal B cell subsets

人类胎儿/新生儿 B 细胞亚群的干细胞起源

• 批准号: 10159198
• 负责人: KISHORE R ALUGUPALLI
• 金额: $ 19.5万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159198
• 关键词: Adult; Antibody Response; Antigens; Autoimmune; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bacterial Infections; Bacterial Polysaccharides; Binding Proteins; Biological; Bone Marrow; Bone Marrow Purging; CD34 gene; Cell Compartmentation; Cell Lineage; Cell surface; Cells; Characteristics; Child; Clinical; Cytokine Receptors; Data; Development; Disease; Ectopic Expression; Encapsulated; Fetal Liver; Fractionation; Genetic Translation; Grant; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell subsets; Hematopoietic stem cells; Human; Human Characteristics; Immune; Immune response; Immune system; Immunoglobulin M; Immunologic Deficiency Syndromes; Knock-out; Licensing; Life; Lymphoid; Lymphopoiesis; Malignant Neoplasms; Mature B-Lymphocyte; MicroRNAs; Molecular; Mus; Natural Killer Cells; Natural regeneration; Neonatal; Newborn Infant; Patients; Phenotype; Play; Polysaccharides; Population; Property; Proteins; RNA; Regulation; Role; Sampling; Source; System; T-Lymphocyte; Testing; Tissues; Transplantation; Umbilical Cord Blood; Ursidae Family; Virus Diseases; cell type; clinically significant; fetal; hematopoietic stem cell differentiation; immune reconstitution; innovation; mouse model; neonatal human; neonate; novel strategies; reconstitution; response; self-renewal; stem; stem cells; transplantation therapy

ABSTRACT It was originally thought that all immune cells were derived from a single hematopoietic stem cell (HSC). However, it is now clear that the mouse B1a B cell subset and the follicular (B2) B cell subset are derived from different HSCs that reside in fetal liver (FL) and adult bone marrow (BM), respectively. There is also mounting evidence that B cells with the cell surface phenotype of B1b and marginal zone (MZ) B cell subsets can be derived from both FL and adult BM in mice, but whether the B cells derived from these different sources have distinct properties is unclear. Whether this situation is recapitulated in humans is not known. However, we have shown that total CD34+ HSCs mobilized from adult human BM cannot effectively reconstitute a B cell compartment when transplanted into severely immune deficient (NOD/SCID/common cytokine receptor  chain knockout; NSG) mice. In contrast, FL and umbilical cord blood (UCB) CD34+ cells are efficient in this regard but give rise to a B cell compartment that phenotypically and functionally resembles that of human newborns and young children. The Lin28b miRNA binding protein has been shown to play a major role in regulating the differentiation potential of the mouse HSCs that give rise to B1a B cells and other “innate-like” lymphoid subsets (the “fetal/neonatal” lineages). Strikingly, when HSCs from adult mouse BM are transduced to express Lin28b they are licensed to give rise to B1a B cells and other fetal/neonatal lymphoid lineages in myeloablated host mice. A potential role for multiple HSC types and Lin28b regulation of HSC differentiation potential has not been investigated in humans. However, Lin28b is expressed in human FL and UCB HSCs but is not detectable in human BM. Moreover, patients that undergo transplantation with HSCs derived from mobilized BM HSCs after myeloablation therapy do not mount robust antibody responses to many antigens and are very susceptible to viral and bacterial infections. Certain antibody responses in mice are predominantly produced by the fetal/neonatal B cell subsets. In total, these data suggest the hypothesis that adult human BM HSCs lack the ability to reconstitute the fetal/neonatal B cell lineages due to absence of the appropriate HSC subset. Moreover, we suggest that, as is the case in mice, adult BM HSCs can be licensed to reconstitute the fetal/neonatal B cell lineages via enforced expression of Lin28b.

摘要 最初认为所有的免疫细胞都来自单一的造血干细胞(HSC)。 然而，现在很清楚的是，小鼠B1a B细胞亚群和滤泡(B2)B细胞亚群源自 不同的HSCs分别存在于胎肝(FL)和成人骨髓(BM)。也有越来越多的 有证据表明，具有B1B细胞表面表型和边缘带(MZ)B细胞亚群的B细胞 来自小鼠的FL和成年BM，但来自这些不同来源的B细胞是否有 不同的属性尚不清楚。目前尚不清楚这种情况是否会在人类身上重演。然而，我们 研究表明，从成人骨髓中动员的CD34+HSCs不能有效地重建B细胞 移植到严重免疫缺陷(NOD/SCID/共同细胞因子受体链)的隔室 基因敲除；NSG)小鼠。相比之下，FL和脐带血CD34+细胞在这方面是有效的 但会产生一个表型和功能与人类新生儿相似的B细胞室 和年幼的孩子。Lin28b miRNA结合蛋白已被证明在调节 小鼠造血干细胞分化为B1a-B细胞和其他“先天类”淋巴样细胞的潜能 子集(“胎儿/新生儿”谱系)。令人惊讶的是，当成年小鼠骨髓的HSCs被转导到表达 LIN28b它们被许可在骨髓清除术中产生B1a B细胞和其他胎儿/新生儿淋巴谱系 寄主老鼠。多种HSC类型的潜在作用及Lin28b对HSC分化潜能的调节 没有在人类身上进行过研究。然而，Lin28b在人FL和UCB HSCs中表达，但不表达 在人类骨髓中可检测到。此外，接受造血干细胞移植的患者来自动员 骨髓间充质干细胞在清髓治疗后不能对许多抗原产生很强的抗体反应，并且非常 易受病毒和细菌感染的。在小鼠体内主要产生某些抗体反应。 通过胎儿/新生儿B细胞亚群。总而言之，这些数据表明，成人骨髓造血干细胞 由于缺乏适当的HSC亚群，缺乏重建胎儿/新生儿B细胞系的能力。 此外，我们建议，就像在小鼠身上一样，成年的骨髓造血干细胞可以被许可重建 胎儿/新生儿B细胞系通过增强表达Lin28b。