Stem cell origins of human fetal/neonatal B cell subsets

摘要 最初认为所有的免疫细胞都来源于单个造血干细胞（HSC）。 然而，现在清楚的是，小鼠B1 a B细胞亚群和滤泡（B2）B细胞亚群来源于 不同的HSC分别存在于胎儿肝脏（FL）和成人骨髓（BM）中。此外， 具有B1 B和边缘区（MZ）B细胞亚群的细胞表面表型的B细胞可被 来源于小鼠FL和成年BM，但是否来自这些不同来源的B细胞具有 不同的属性不清楚。这种情况是否在人类中重演尚不清楚。但我们 已经显示从成人BM动员的总CD 34 + HSC不能有效地重建B细胞 当移植到严重免疫缺陷（NOD/SCID/共同细胞因子受体β链）的细胞中时， 敲除; NSG）小鼠。相反，FL和脐带血（UCB）CD 34+细胞在这方面是有效的 但产生了在表型和功能上类似于人类新生儿的B细胞区室 和年幼的孩子。Lin 28 b miRNA结合蛋白已被证明在调节细胞凋亡中起主要作用。 小鼠HSC的分化潜力，产生B1 a B细胞和其他“先天性”淋巴细胞 亚群（“胎儿/新生儿”谱系）。引人注目的是，当来自成年小鼠BM的HSC被转导以表达 Lin 28 B，它们被许可在骨髓清除中产生B1 a B细胞和其他胎儿/新生儿淋巴谱系。 宿主小鼠。多种HSC类型和Lin 28 b调节HSC分化潜能的潜在作用， 尚未在人类中进行过研究。然而，Lin 28 b在人FL和UCB HSC中表达，而在人FL和UCB HSC中不表达。 在人骨髓中可检测到。此外，接受动员的HSC移植的患者， 骨髓消融治疗后的BM HSC对许多抗原不产生强烈的抗体应答，并且非常敏感。 易受病毒和细菌感染。小鼠体内的某些抗体反应主要由 胎儿/新生儿B细胞亚群。总的来说，这些数据表明，成人骨髓造血干细胞 缺乏重建胎儿/新生儿B细胞谱系的能力。 此外，我们认为，与小鼠的情况一样，成年骨髓造血干细胞可以被授权重建造血干细胞。 胎儿/新生儿B细胞谱系通过Lin 28 B的强制表达。

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.