Developmental Stage-Related Changes in Lymphopoiesis

说明(申请人提供)：免疫系统最初是通过将造血干细胞分化为各种类型的淋巴细胞来形成和补充的。最近发展起来的转基因小鼠现在使研究干细胞早期分化为淋巴系命运成为可能，将基因表达、功能和表面标记的变化与RAG-1基因座的激活联系起来。随着有关成人骨髓中事件顺序的信息积累，越来越明显的是，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位置，但这些群体与成人骨髓中的相应群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是由仅用于胎儿淋巴细胞产生的分化机制造成的。我们将绘制小鼠胚胎中最早的淋巴祖细胞的出现图，将它们的特征与成人的特征进行比较。移植和培养实验可能会将许多差异归因于胎儿和成人环境中的居住、接触独特的分化线索和/或最近干细胞的增殖。胚胎中淋巴祖细胞的其他特性可能是固有的，并与它们来自胎儿干细胞而不是成人干细胞有关。我们将使用新的转基因动物模型来检验这一假设，即早期出现的造血干细胞被后来出现的干细胞取代。由此产生的信息可能会为提高新生儿免疫力、治疗免疫缺陷和恢复移植后的淋巴细胞提供新的方法。它还将在干细胞发展变化的更广泛背景下有用，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能被用来为他们的成年同行提供优势或人为地赋予他们。此外，这种类型的基础研究可以为新生儿对淋巴细胞白血病的敏感性提供解释。

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.