Developmental Stage-Related Changes in Lymphopoiesis

描述（由申请人提供）：免疫系统最初通过造血干细胞分化为各种类型的淋巴细胞而形成和补充。最近开发的基因敲入小鼠现在可以研究干细胞到淋巴样命运的早期特化，将基因表达，功能和表面标志物的变化与RAG-1基因座的激活相关联。随着有关成人骨髓中事件顺序的信息积累，越来越清楚的是，它与胎儿/新生儿过程有很大不同。干细胞出现在胚胎生命中的至少两个部位，但这些群体与成人骨髓中的对应物之间的发育关系仍然知之甚少。新生儿免疫系统的独特特征和局限性可能来自仅用于胎儿淋巴细胞产生的分化机制。我们将绘制小鼠胚胎中最早的淋巴祖细胞的出现，比较和对比它们与成年人的特征。移植和培养实验可能将许多差异归因于胎儿与成人环境中的居住、暴露于独特的分化线索和/或干细胞的近期增殖。胚胎中淋巴祖细胞的其他特性可能是内在的，并且与它们来自胎儿而不是成人干细胞的起源有关。我们将使用新的转基因动物模型来检验早期出现的造血干细胞被后来出现的造血干细胞所取代的假设。由此产生的信息可能会提出新的方法来增强新生儿免疫力，治疗免疫缺陷和恢复淋巴细胞移植后。在干细胞发育变化的更广泛背景下，它也将是有用的，突出了再生医学的局限性和机会。例如，胎儿干细胞的所需特性可用于有利地或人工地赋予其成人对应物。此外，这种类型的基础研究可以解释新生儿对淋巴细胞白血病的敏感性。

DESCRIPTION (provided by applicant): The immune system is initially formed and replenished by differentiation of hematopoietic stem cells into various types of lymphocytes. Recently developed knock-in mice now make it possible to study early specification of stem cells into lymphoid fates, correlating changes in gene expression, function and surface markers with activation of the RAG-1 locus. As information accumulates about the sequence of events in adult bone marrow, it has become increasingly clear that it differs substantially from the fetal/neonatal process. Stem cells emerge in at least two sites in embryonic life, but developmental relationships between those populations and their counterparts in adult marrow remain poorly understood. Unique features and limitations to the newborn immune system could result from differentiation mechanisms that are only used for fetal lymphocyte production. We will chart emergence of the earliest lymphoid progenitors in murine embryos, comparing and contrasting their characteristics with ones in adults. Transplantation and culture experiments may attribute many differences to residence in fetal versus adult environments, exposure to unique differentiation cues and/or the recent proliferation of stem cells. Other properties of lymphoid progenitors in embryos may be intrinsic and related to their origin from fetal, rather than adult, stem cells. We will use new transgenic animal models to test the hypothesis that early emerging hematopoietic stem cells are replaced by ones that arise later. The resulting information may suggest new ways to augment neonatal immunity, treat immunodeficiency and restore lymphocytes following transplantation. It will also be useful within a broader context of developmental changes in stem cells, highlighting limitations and opportunities in regenerative medicine. For example, desirable properties of fetal stem cells may be used to advantage or artificially conferred on their adult counterparts. Furthermore, basic investigation of this type could provide explanations for the sensitivity of neonates to lymphocytic leukemia.