Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging

造血干细胞（HSC）的功能在发育和衰老过程中发生显著变化。 与年轻的HSC相比，老年HSC具有低的和骨髓偏向的再生潜力。骨髓- HSC的偏向分化被假定为至少部分地对受损的适应性分化负责。 免疫系统在老年人中观察到，老年人的一个重要健康问题是， 传染病目前流行的观点是HSC的老化受HSC内在和外在的双重调控 变化理解HSC衰老如何受到细胞外在变化影响的一个重要障碍是， 衰老影响多个器官，HSC受多个器官和细胞类型的调节。 骨髓中的HSC支持微环境（HSC龛）。在这里，我们建议剖析复杂的 衰老的生物学，通过将年龄相关的变化引入HSC生态位内的一种细胞类型，即间充质细胞， 基质细胞（MSC），并确定MSC的变化是否引起HSC的年龄相关变化， 造血我们已经发现，抗衰老因子Bmi 1在MSC中高度表达， Bmi 1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 从MSC中有条件地删除Bmi 1会导致骨髓中的衰老和脂肪细胞扩增， 类似于人类衰老的过程。这些与年龄相关的MSC功能变化引起了年龄相关的 HSC和造血功能的变化，包括贫血、骨髓细胞减少，以及显著的髓样细胞减少， HSCs的偏向性分化。HSC和造血的所有这些变化都是老年人衰老的标志。 造血干细胞与造血因此，我们假设，通过删除Bmi 1诱导的MSC中的年龄相关变化， 导致HSC中与年龄相关的变化。我们的长期目标是了解HSC衰老是如何被细胞调节的 被HSC niche超越。我们的新模式提供了一个独特的机会，专注于HSC的变化 特别是骨髓间充质干细胞的变化引起的功能。我们有两个广泛的目标来研究Bmi 1如何在 MSC调节HSC和造血。在目标1中，我们将确定HSC和造血功能是否 从MSC中删除Bmi 1后的表型随着年龄的增长或炎症而恶化。我们 还将检查HSC植入和动员是否也受到MSC中删除Bmi 1的影响。在 目的2，我们将确定是否诱导衰老或脂肪形成后，Bmi 1删除从MSC 通过有条件地删除衰老调节因子Ink 4a/Arf或脂肪生成， 调节因子PPARγ和Prdm 16。我们还将研究Bmi 1调节细胞凋亡的分子机制。 PPARγ和Prdm 16。在完成这项工作后，我们将有一个深刻的了解如何在HSC的变化， MSC功能改变诱导的小生境引起HSC中与年龄相关的变化。这可能会导致新的 体外和体内MSC增强HSC功能干预及老年人更好的预处理方案 骨髓移植受者通过改善MSC功能来增加HSC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.