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，其中淋巴细胞和骨髓细胞不断地分化， 在一生中以恒定的比例产生。现在很明显，情况并非如此， 随着年龄的增长，B细胞发育下降，而骨髓生成保持相对完整。这反过来 被认为是导致老年人对感染的易感性增加和 预防针这一建议的中心假设是，与年龄相关的脂肪细胞的积累， 髓腔中的浆细胞损害造血微环境的能力， 淋巴细胞生成与此相反，骨髓生成要么抵抗这些变化的环境，要么被这些变化的环境刺激。 动力学在出生时，大部分骨髓被称为"红"骨髓，以表明它是一个活跃的部位。 造血然而，随着年龄的增长，脂肪细胞的积累和非- 造血“黄”髓。骨髓脂肪细胞的积累是一个渐进的过程，我们 当这种情况发生时，淋巴细胞生成优先受到抑制，而骨髓细胞生成保持相对完整。 目标1中的实验将使用体内和体外系统来测试这一假设，我们还将分析 PPAR-γ +/-小鼠中的造血模式，其骨髓中具有高度显著的减少 脂肪细胞，随着时间的推移预期与年龄相关的B淋巴细胞生成下降在本研究中将不那么严重。 因为他们缺乏脂肪细胞。骨髓脂肪细胞为浆细胞提供了支持性的小生境。在 鉴于其数量随年龄增长而增加，我们认为浆细胞也可能增加 随着时间的推移，发现情况确实如此。这具有重要的意义，因为浆细胞是一个来源， 许多已知抑制B淋巴细胞生成的炎性细胞因子。目标2中的实验将检验这一假设 这种浆细胞的增加也有助于淋巴细胞发育中与年龄相关的减少。我们将 建立在显示浆细胞与造血干细胞（HSC）共定位于造血干细胞中的初步数据的基础上， 骨髓，并评估浆细胞来源的信号的潜力，以扭曲的发展潜力， 造血干细胞向骨髓细胞转化。我们还将产生缺乏浆细胞的Cd19-Cre; flPrdm1fl小鼠， 确定这些动物中B淋巴细胞生成的下降是否随时间而不那么急剧。一个关键问题， 翻译的观点是淋巴细胞生成是否可以在老年人中恢复活力。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的药物和抗体 消耗浆细胞，使老年人的B淋巴细胞再生。进一步的实验将确定， 这些干预靶向HSC并影响其中的基因表达模式。总的来说，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， 干预性靶点，可能具有恢复老年人免疫力的转化潜力。

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.