Developmental Stage-Related Changes in Lymphopoiesis

描述（由申请人提供）：免疫系统通过造血干细胞分化为各种类型的淋巴细胞而初步形成和补充。最近开发的敲入小鼠现在可以研究干细胞进入淋巴细胞命运的早期特征，将基因表达、功能和表面标记物的变化与RAG-1位点的激活联系起来。随着关于成人骨髓事件序列的信息积累，越来越清楚的是，它与胎儿/新生儿的过程有很大的不同。干细胞在胚胎生命中至少出现在两个部位，但这些细胞群与它们在成人骨髓中的对应体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源于仅用于胎儿淋巴细胞产生的分化机制。我们将绘制最早的淋巴祖细胞在小鼠胚胎中出现的图表，并将其与成人的特征进行比较和对比。移植和培养实验可能将许多差异归因于胎儿和成人环境的不同，暴露于独特的分化线索和/或干细胞最近的增殖。胚胎中淋巴祖细胞的其他特性可能是内在的，与它们来自胎儿干细胞而不是成体干细胞有关。我们将使用新的转基因动物模型来验证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。由此得到的信息可能为增强新生儿免疫、治疗免疫缺陷和移植后淋巴细胞恢复提供新的途径。它还将在干细胞发育变化的更广泛背景下发挥作用，突出再生医学的局限性和机遇。例如，胎儿干细胞的理想特性可用于优势或人为地赋予其成人干细胞。此外，该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.