Epigenetic Regulation of Mesenchymal Stem Cell Transplantation in Aging

间充质干细胞移植在衰老过程中的表观遗传调控

• 批准号: 9906891
• 负责人: Chi-Der Chen
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-04 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906891
• 关键词: Actomyosin; Address; Adult; Aging; Appearance; Architecture; Binding; Bone Marrow; Cell Aging; Cell Communication; Cell Lineage; Cell Therapy; Cells; Cellular Morphology; Chemicals; Complex; Data; Deterioration; Disease; F-Actin; Face; Femur; Functional disorder; Future; G9a histone methyltransferase; Gene Expression Profiling; Genetic; Genetic Transcription; Goals; Health; Hematopoietic; Heterochromatin; Histones; Homeostasis; Immunofluorescence Immunologic; Impairment; Infusion procedures; Knowledge; Lead; Life; Link; Longevity; Lysine; Maintenance; Mammalian Cell; Marrow; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methylation; MicroRNAs; Modeling; Molecular; Morphology; Mus; Nuclear; Nuclear Protein; Nuclear Structure; Organ; Osteogenesis; Osteopenia; Osteoporosis; Pathogenicity; Pathway interactions; Phenotype; Physiological; Procedures; Process; Proteins; Proteomics; Regenerative Medicine; Rejuvenation; Reporter; Role; SIRT1 gene; Shapes; Skeletal system; Skeleton; Small Interfering RNA; Stains; Structure; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Transmission Electron Microscopy; alpha Karyopherins; base; bone; bone loss; craniofacial bone; demethylation; disease phenotype; epigenetic regulation; epigenetic therapy; epigenome; exhaustion; extracellular vesicles; hematopoietic stem cell niche; histone methyltransferase; histone modification; human disease; improved; inhibitor/antagonist; metabolome; novel; novel therapeutics; overexpression; promoter; protein transport; public health relevance; scaffold; self-renewal; senescence; stem cell therapy; stem cells; success; tissue regeneration; tool; transcriptome sequencing; translational study; vector

Project Description Aging leads a deterioration of the physiological systems and is a paradigmatic example of homeostasis collapse. Changes in the facial skeleton, as well as other skeletal system that occur with aging and their impact on facial appearance have not been well appreciated, which largely limited the potential benefit of rejuvenation procedures. To delay aging and maintain body homeostasis, continual tissue renewal and regeneration are necessary, which is mainly attributed to somatic stem cells. Loss of bone architecture remodeling and osteo- lineage cells is hallmark of aging, indicating that maintenance of bone marrow niche by bone marrow mesenchymal stem cells (MSCs) may contribute to bone homeostasis and slowing aging. MSC transplantation (MSCT) transfers multiple cellular components to host cells that are able to ameliorate a variety of diseases via genetic and epigenetic regulations. However, it has remained unknown whether MSCT can rescue impaired cells residing in an aging microenvironment and thereby extend mammalian lifespan. In many mammalian cells, cellular senescence is characterized by several molecular and cellular markers, such as a large flat morphology and formation of senescence-associated heterochromatin foci (SAHF). Changes in histone modifications have been linked to stabilizing nuclear F-actin scaffold and actomyosin contractility, suggesting nuclear size and shape may be regulated by specific histone signatures. The goal of this proposal is to investigate how transplanted MSCs participate in rejuvenation of host senescent cells via histone modifications. My preliminary data show that histone methyltransferase (HMT) G9a/GLP tri-methylates H3K9 residues, which mediate formation of heterochromatin structure in senescent MSCs. MSCT significantly rescues impaired host senescent MSCs and extends the lifespan in aging mice through reusing lysine-specific demethylase 4C (KDM4C) to demethylate H3K9me3. The central hypothesis of this proposal is that KDM4C transfer from donor to recipient MSCs demethylates H3K9me3 to rescue SAHF structure, and that the transfer of KDM4C regulates Sirt1 promoter activation to ameliorate aging-associated osteoporosis for lifespan extension. During this proposal, I will explore the interactions between H3K9me3 histone signatures and Sirt1 promoter to address how MSC-based therapy is crucial for delay aging (Aim 1). Since KDM4C demethylates H3K9me3 for SIRT1 activation and MSC rejuvenation, I will determine the effects of HMT inhibitors for rescuing senescent MSCs (Aim 2). Upon successful completion of the Specific Aims, this translational study will extend our knowledge of aging processes and describe detailed mechanisms of MSC-based therapy for lifespan elongation. The findings from this proposal may lead us to develop a novel H3K9me3 suppressive molecule-based therapy to manage MSC rejuvenation for epigenome-mediated bone regenerative medicine. ! !

项目描述 衰老导致生理系统恶化，是体内稳态的一个范式例子 坍塌。面部骨骼的变化以及其他随着衰老及其影响而发生的骨骼系统 在面部外观上，人们没有得到很好的赞赏，这在很大程度上限制了恢复活力的潜在好处 程序。为了延迟衰老并保持身体体内平衡，持续的组织更新和再生是 必要的，这主要归因于体干细胞。骨骼结构的损失和骨 - 谱系细胞是衰老的标志，表明骨髓维持骨髓生态位 间充质干细胞（MSC）可能有助于骨稳态和减慢衰老。 MSC移植 （MSCT）将多个细胞成分转移到能够通过 遗传和表观遗传法规。但是，MSCT是否可以挽救受损 居住在老化的微环境中，从而延长哺乳动物寿命的细胞。在许多哺乳动物细胞中， 细胞衰老的特征是几个分子和细胞标记，例如大平坦 衰老相关异染色质灶（SAHF）的形态和形成。组蛋白的变化 修改已与稳定核F-肌动蛋白支架和肌动球蛋白收缩性有关，这表明 核大小和形状可以通过特定的组蛋白特征来调节。该提议的目的是 研究移植的MSC如何通过组蛋白修饰参与宿主衰老细胞的恢复活力。 我的初步数据表明，组蛋白甲基转移酶（HMT）G9A/GLP三甲基盐H3K9残基 衰老MSC中异染色质结构的介导。 MSCT大大拯救受损害的主机 通过重复赖氨酸特异性脱甲基酶4C，衰老的MSC并延长老化小鼠的寿命 （KDM4C）将脱甲基H3K9me3。该提议的中心假设是KDM4C从 接受者MSC的供体脱甲基H3K9me3以营救SAHF结构，并转移 KDM4C调节SIRT1启动子激活以改善与衰老相关的骨质疏松症的寿命 扩大。在此提案中，我将探讨H3K9me3组蛋白签名与SIRT1之间的相互作用 启动子解决基于MSC的治疗对于延迟衰老至关重要（AIM 1）。由于kdm4c脱甲基 H3K9me3用于SIRT1激活和MSC恢复，我将确定HMT抑制剂对 营救衰老MSC（AIM 2）。成功完成特定目标后，这项翻译研究 将扩展我们对衰老过程的了解，并描述基于MSC的治疗的详细机制 寿命伸长。该提案的发现可能会导致我们开发出一种新颖的H3K9me3抑制作用 基于分子的治疗，用于管理表观基因组介导的骨再生医学的MSC恢复活力。 呢 呢