Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging

在发育和衰老过程中，造血干细胞(HSC)的功能会发生显著的变化。 与年轻的HSCs相比，老年HSCs的再生能力较低且偏重于髓系。这个髓细胞- HSC的偏向分化被认为至少对适应性受损负有部分责任 在老年人中观察到免疫系统，这是老年人关注的一个重大健康问题，增加了 传染病。主流观点认为，HSC的衰老受HSC内在和外在两方面的调节 改变。理解细胞外源性变化如何影响HSC老化的一个重要障碍是 衰老影响多个器官，HSCs受体内多个器官和细胞类型的调节 骨髓中支持HSC的微环境(HSC生态位)。在这里，我们建议解剖这个建筑群 通过将与年龄相关的变化引入HSC生态位内的一种细胞类型--间充质--的衰老生物学 基质细胞(MSCs)，并确定MSCs的变化是否会导致HSCs和HSCs的年龄相关变化 造血术。我们发现一种抗衰老因子Bmi1在MSCs中的表达水平高于 Bmi1在骨髓中的表达水平随着年龄的增长而下降。然后我们发现 有条件地从骨髓间充质干细胞中删除Bmi1会导致骨髓中脂肪细胞的衰老和扩张， 类似于人类衰老过程中发生的情况。这些与年龄相关的MSC功能变化导致了与年龄相关的 HSC和造血的变化，包括贫血，骨髓细胞丢失，尤其是髓系- 肝星状细胞的偏向分化。所有这些在HSCs和造血方面的变化都是衰老的标志 造血干细胞与造血。因此，我们假设Bmi1基因缺失会导致骨髓间充质干细胞发生与年龄相关的变化 导致肝星状细胞的年龄相关变化。我们的长期目标是了解HSC衰老是如何调节细胞的 外在的由HSC利基公司提供。我们的新模式提供了一个关注HSC变化的独特机会 功能是由骨髓间充质干细胞的变化引起的。我们有两个广泛的目标来研究Bmi1如何在 MSCs调节HSCs和造血。在目标1中，我们将确定HSC与造血 从MSCs中删除Bmi1后的表型会随着年龄的增加或炎症而恶化。我们 还将研究从MSCs中删除Bmi1是否也会影响HSC的植入和动员。在……里面 目的2，我们将确定骨髓间充质干细胞Bmi1缺失后是否诱导衰老或成脂 通过有条件地删除衰老调节因子Ink4a/Arf或脂肪生成来损害HSC的利基功能 监管机构PPARγ和Prdm16。我们还将研究Bmi1调控的分子机制 PPARγ和Prdm16.这项工作完成后，我们将对HSC的变化有一个深刻的了解 MSC功能改变引起的小生境导致HSC的年龄相关变化。这可能会导致小说的产生 通过体内和体外间充质干细胞提高HSC功能的干预和更好的老年预适应方案 骨髓移植受者通过改善MSC功能来增加HSC的植入和功能。

Hematopoietic stem cell (HSC) function undergoes significant changes during development and upon aging. Aged HSCs have low and myeloid-biased regenerative potential compared to young HSCs. This myeloid- biased differentiation of HSCs is postulated to be at least partially responsible for the impaired adaptive immune system observed in elder population, a significant health concern for elders increasing the incidence of infectious diseases. The prevailing view is that HSC aging is regulated by both HSC intrinsic and extrinsic changes. A significant barrier in understanding how HSC aging is affected by cell extrinsic changes is the fact that aging affects multiple organs, and that HSCs are regulated by multiple organs and cell types within the HSC supportive microenvironment (HSC niche) in the bone marrow. Here, we propose to dissect the complex biology of aging by introducing age-related changes to one cell type within the HSC niche, the mesenchymal stromal cells (MSCs), and determine whether changes in MSCs cause age-related changes in HSCs and hematopoiesis. We have found that an anti-senescence factor Bmi1 is highly expressed in MSCs compared to other cells in the bone marrow, and that Bmi1 expression levels in MSCs decline with age. We then discovered that conditionally deleting Bmi1 from MSCs causes senescence and expands adipocytes in the bone marrow, similar to what happens in human aging. These age-related changes in MSC function caused age-related changes in HSC and hematopoiesis, including anemia, loss of bone marrow cellularity, and strikingly, myeloid- biased differentiation of HSCs. All of these changes in HSCs and hematopoiesis are hallmarks of aging in HSCs and hematopoiesis. We thus hypothesized that age-related changes induced in MSCs by deleting Bmi1 causes age-related changes in HSCs. Our long term goal is to understand how HSC aging is regulated cell extrinsically by the HSC niche. Our new model provides a unique opportunity to focus on changes in HSC function caused specifically by changes in bone marrow MSCs. We have two broad aims to study how Bmi1 in MSCs regulate HSCs and hematopoiesis. In aim 1, we will determine whether the HSC and hematopoiesis phenotypes after deleting Bmi1 from MSCs become exacerbated with advanced age or by inflammation. We will also examine whether HSC engraftment and mobilization are also affected by deleting Bmi1 from MSCs. In aim 2, we will determine whether induction of senescence or adipogenesis upon Bmi1 deletion from MSCs impairs the HSC niche function, by conditionally deleting senescence regulators Ink4a/Arf, or adipogenesis regulators PPARγ and Prdm16. We will also examine the molecular mechanism by which Bmi1 regulates PPARγ and Prdm16. Upon completion of this work, we will have a deep understanding of how changes in HSC niche induced by altered MSC function causes age-related changes in HSCs. This may lead to novel intervention to increase HSC function via MSC in vitro and in vivo, and better conditioning regimens for elder bone marrow transplant recipients to increase HSC engraftment and function by improving MSC function.