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