Effects of Age-Related Changes in the Microenvironment on Patterns of Hematopoiesis

摘要 造血通常被认为是一个统一的过程，在这个过程中，淋巴样细胞和髓样细胞不断地 在一生中以恒定的比例产生。现在很明显，情况并非如此，有了 随着年龄的增长，B细胞的发育有所下降，而骨髓生成相对完好。这又反过来 被认为导致老年人对感染的易感性增加，并降低了 接种疫苗。这一建议的中心假设是与年龄相关的脂肪细胞和 髓腔内的浆细胞损害了造血微环境的支持能力 淋巴生成。相比之下，骨髓生成要么抵抗这些变化的环境，要么受到它们的刺激。 动力学。出生时，大部分骨髓被称为“红色”骨髓，表明它是一个活跃的部位。 造血术。然而，随着年龄的增长，脂肪细胞会积聚，并形成非 造血的“黄色”骨髓。骨髓脂肪细胞的积累是一个渐进的过程，我们 提出，当这种情况发生时，淋巴细胞生成优先受到抑制，而骨髓生成保持相对完整。 目标1中的实验将使用体内和体外系统来验证这一假设，我们还将分析 骨髓显著减少的PPAR-γ+/-小鼠的造血模式 随着时间的推移，脂肪细胞。预计与年龄相关的B淋巴细胞生成下降在这一领域将不那么严重 由于脂肪细胞缺乏而产生的菌株。骨髓脂肪细胞为浆细胞提供了一个支持性的利基。在……里面 鉴于它们的数量随着年龄的增长而增加，我们考虑了浆细胞也可能增加的可能性 随着时间的推移，发现情况就是这样。这具有重要的意义，因为浆细胞是 许多已知的炎性细胞因子抑制B淋巴细胞的生成。目标2中的实验将检验这一假设 浆细胞的这种增加也有助于与年龄相关的淋巴细胞发育的减少。我们会 根据初步数据显示，血浆细胞与造血干细胞(HSCs)共存于 并评估浆细胞来源的信号是否有可能扭曲儿童的发育潜能 造血干细胞向造血祖细胞方向发展。我们还将产生CD19-Cre；flPrdm1fl小鼠，它们缺乏浆细胞和 确定这些动物的B淋巴细胞生成能力是否随着时间的推移而下降得不那么剧烈。来自一位 翻译的角度是老年人的淋巴生成是否可以恢复活力。AIM中的实验 3将测试各种干预措施的能力，其中包括抑制脂肪细胞形成和抗体的药物 这会耗尽浆细胞，恢复老年人的B淋巴细胞生成能力。更多的实验将确定 这些干预措施针对的是造血干细胞，并影响它们的基因表达模式。总而言之，这些数据 在拟议的研究中获得的结果将增加对衰老如何影响造血的理解，并确定 可能具有翻译潜力以恢复老年人免疫力的干预靶点。

Abstract Hematopoiesis is often viewed as a uniform process in which lymphoid and myeloid cells are continually generated in constant proportions throughout life. It is now evident that this is not the case and that, with increasing age, there is a decline in B cell development while myelopoiesis remains relatively intact. This in turn is thought to contribute to the increased susceptibility of the elderly to infection and the reduced efficacy of vaccination. The central hypothesis of this proposal is that the age-related accumulation of adipocytes and plasma cells in the medullary cavity impairs the capacity of the hematopoietic microenvironment to support lymphopoiesis. In contrast, myelopoiesis is either resistant to or is stimulated by these changing environmental dynamics. At birth most of the bone marrow is referred to as “red” marrow to indicate that it is a site of active hematopoiesis. However, with increasing age there is an accumulation of adipocytes and the formation of non- hematopoietic “yellow” marrow. The accumulation of bone marrow adipocytes is a gradual process, and we propose that as this occurs, lymphopoiesis is preferentially inhibited while myelopoiesis remains relatively intact. Experiments in Aim 1 will test this hypothesis using both in vivo and in vitro systems, and we will also analyze patterns of hematopoiesis in PPAR-γ+/– mice, which have a highly significant diminution in bone marrow adipocytes, over time. The expectation is that age-related declines in B lymphopoiesis will be less severe in this strain due to their adipocyte deficiency. Bone marrow adipocytes provide a supportive niche for plasma cells. In view of their increase in number with age, we considered the possibility that plasma cells might also increase over time and found this to be the case. This has significant implications, as plasma cells are a source of numerous inflammatory cytokines known to inhibit B lymphopoiesis. Experiments in Aim 2 will test the hypothesis that this increase in plasma cells also contributes to age-related reductions in lymphocyte development. We will build upon preliminary data showing that plasma cells co-localize with hematopoietic stem cells (HSCs) in the bone marrow and evaluate the potential of plasma cell derived signals to skew the developmental potential of HSCs towards myelopoiesis. We will also generate Cd19-Cre;flPrdm1fl mice which lack plasma cells and determine if declines in B lymphopoiesis in these animals are less precipitous over time. A key question from a translational perspective is whether lymphopoiesis can be rejuvenated in old individuals. The experiments in Aim 3 will test the ability of various interventions, which include drugs that inhibit adipocyte formation and antibodies that deplete plasma cells, to rejuvenate B lymphopoiesis in the elderly. Additional experiments will determine if these interventions target HSCs and affect patterns of gene expression in them. Taken together, the data obtained in the proposed studies will increase the understanding of how aging affects hematopoiesis and identify interventional targets that may have translational potential for rejuvenating immunity in the elderly.