Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging

间充质基质细胞调节造血干细胞衰老

基本信息

批准号：
9189715
负责人：
Daisuke Nakada
金额：
$ 43.13万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189715
关键词：
Adaptive Immune System Address Adipocytes Affect Age Aging Alpha Cell Anemia Biological Markers Biology of Aging Bone Marrow Bone Marrow Aspiration Bone Marrow Cells Bone Marrow Transplantation Cell Aging Cell Line Cell Maintenance Cell physiology Cells Communicable Diseases Complex Deterioration Development Elderly Engraftment Environment Goals Health Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Impairment In Vitro Incidence Inflammation Intervention Lead Lymphoid Cell Mediating Mesenchymal Mesenchymal Differentiation Methods Modeling Molecular Mus Myelogenous Myeloid Cells Myelopoiesis Organ Osteoblasts PPAR gamma Pancytopenia Phenotype Polycomb Population Proteins Regimen Role Stem cells Stress Stromal Cells System Testing Tissues Transplant Recipients Transplantation Up-Regulation Work age related aged bone bone loss cell type conditioning genetic approach immune system function improved functioning in vivo lipid biosynthesis mouse model novel reconstitution regenerative senescence young adult

项目摘要

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.

造血干细胞 (HSC) 功能在发育过程中和衰老过程中会发生显着变化。与年轻的 HSC 相比，老年 HSC 的再生潜力较低且偏向骨髓。据推测，HSC 的分化偏差至少是适应性受损的部分原因。在老年人群中观察到的免疫系统是老年人的一个重大健康问题，增加了老年人群的发病率普遍的观点是HSC的衰老受到HSC内在和外在的调节。了解细胞外在变化如何影响 HSC 衰老的一个重要障碍是这一事实。衰老影响多个器官，并且造血干细胞受到体内多个器官和细胞类型的调节在这里，我们建议剖析骨髓中的 HSC 支持微环境（HSC 生态位）。通过向 HSC 生态位内的一种细胞类型（间充质细胞）引入与年龄相关的变化来研究衰老生物学基质细胞 (MSC)，并确定 MSC 的变化是否会导致 HSC 和年龄相关的变化我们发现，与相比，MSCs 中抗衰老因子 Bmi1 高表达。骨髓中的其他细胞，并且 MSC 中的 Bmi1 表达水平随着年龄的增长而下降。有条件地从 MSC 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情况。 HSC 和造血功能的变化，包括贫血、骨髓细胞结构丧失，以及引人注目的骨髓细胞减少 HSC 和造血功能的所有这些变化都是衰老的标志。因此，我们通过删除 Bmi1 来阻止 MSC 中诱导的年龄相关变化。导致 HSC 发生与年龄相关的变化，我们的长期目标是了解 HSC 衰老是如何受到细胞调节的。我们的新模式提供了一个独特的机会来关注 HSC 的变化。我们有两个广泛的目标来研究 Bmi1 如何在骨髓中发挥作用。 MSCs 调节 HSCs 和造血作用在目标 1 中，我们将确定 HSCs 和造血作用是否存在。从 MSC 中删除 Bmi1 后，表型会随着年龄的增长或炎症而加剧。还将检查从 MSC 中删除 Bmi1 是否也会影响 HSC 的植入和动员。目标 2，我们将确定从 MSC 中删除 Bmi1 是否会诱导衰老或脂肪形成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 生态位功能我们还将研究 Bmi1 调节的分子机制。完成这项工作后，我们将深入了解 HSC 的变化。 MSC 功能改变引起的 HSC 生态位发生与年龄相关的变化，这可能会导致新的变化。通过 MSC 进行体内外干预以增强 HSC 功能，并为老年人提供更好的调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。