Epigenetic regulation of autophagy and stemness of MSCs in skeletal aging

骨骼衰老过程中间充质干细胞自噬和干性的表观遗传调控

• 批准号: 10901048
• 负责人: CUN-YU WANG
• 金额: $ 39.27万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901048
• 关键词: ATAC-seq; Adipocytes; Adipose tissue; Affect; Age-Related Bone Loss; Aging; Attenuated; Autophagocytosis; Autophagosome; Bone Marrow; Bone Regeneration; Cell Aging; Cell Count; Cell Separation; Cells; ChIP-seq; Complex; Dental; Dental Implants; Elderly; Epigenetic Process; Excision; Female; Genes; Genetic; Histology; Histone H3; Histones; Homeostasis; Impairment; Iron; Knock-in Mouse; Knock-out; Lysine; Lysosomes; Marrow; Mediating; Mesenchymal; Mesenchymal Differentiation; Molecular; Mus; Natural regeneration; Obesity; Organelles; Osteoblasts; Osteogenesis; Osteoporosis; Osteoporotic; Patients; Persons; Play; Prevention; Process; Reaction; Recycling; Regulation; Rejuvenation; Risk Factors; Role; Signal Pathway; Small Interfering RNA; Stromal Cells; Testing; Therapeutic; Tooth structure; adult stem cell; aged; alpha ketoglutarate; bone; bone aging; bone loss; bone mass; cofactor; craniofacial bone; craniofacial tissue; demethylation; epigenetic regulation; exhaustion; genetic signature; histone demethylase; histone methylation; in vivo; innovation; knock-down; macromolecule; male; novel; novel strategies; oral tissue; orofacial; osteogenic; overexpression; prevent; progenitor; public health relevance; reconstruction; restoration; screening; self-renewal; senescence; skeletal; skeletal stem cell; small molecule; stem; stem cell fate; stem cells; stemness; transcription factor; transcriptome sequencing

Project Summary/Abstract The long-term objectives of this application are to understand epigenetic mechanisms that control long and orofacial bone aging and to explore whether targeting epigenetic factors could help to prevent age-associated bone loss. The age-related bone loss is a critical risk factor for osteoporosis that affects millions of patients worldwide. It also represents a significant challenge for functional reconstruction or regeneration of dental, oral, and craniofacial tissues such as dental implants for replacing missing teeth in elderly people. Bone marrow mesenchymal stromal/stem cells (MSCs) are believed to be the common progenitors for both osteoblasts and adipocytes in bone marrow, but commitments to these two lineages are mutually exclusive. Aging reduces the bone marrow MSC number and its self-renewal, and favors their differentiation into adipocytes at the expense of osteoblasts, resulting in bone loss. Using siRNA screening, we discover that the histone demethylase KDM4B plays a critical role in osteogenic differentiation of MSCs by erasing trimethylated histone H3 at lysine 9 (H3K9me3). The expression of Kdm4b is significantly downregulated in MSCs isolated from aging mice compared to young mice. Very recently, we demonstrate that the knockout of KDM4B in MSCs in vivo exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. To explore whether the induction or activation of KDM4B prevent skeletal aging in vivo, we generated knockin mice overexpressing Kdm4b. Very excitingly, we find that the overexpression of Kdm4b significantly attenuates mouse skeletal aging. Unexpectedly, our RNA-seq analysis reveals that the induction of KDM4B in aged MSCs epigenetically promotes autophagy and inhibits the senescence gene signature in addition to the modulation of cell fate and stemness. Growing evidence shows that autophagy helps to maintain the self-renewal of adult stem cells by preventing their senescence. The impaired autophagy attenuates MSC stemness and promotes MSC senescence and exhaustion in skeletal aging. While key molecules or signaling pathways associated with autophagy have been elucidated, how autophagy in skeletal aging is epigenetically regulated is poorly understood. Based on our exciting novel discoveries, we hypothesize that KDM4B epigenetically regulates autophagy, senescence and self-renewal of MSCs in skeletal aging. We propose to examine whether the induction or activation of KDM4B in aging mice rejuvenates MSCs and prevents skeletal aging by promoting autophagy and stemness using genetic and small molecule approaches. New findings from our studies will have important implications in developing innovative therapeutic strategies for preventing skeletal aging and osteoporosis as well as promoting MSC-mediated bone regeneration.

项目摘要/摘要 这项应用的长期目标是了解控制长期和长期和 探讨靶向表观遗传因素是否有助于预防年龄相关的口腔颌面部骨老化 骨质流失。与年龄相关的骨丢失是影响数百万患者的骨质疏松症的关键危险因素 全世界。它也是对牙科、口腔、 以及用于修复老年人缺失牙齿的牙种植体等头面部组织。骨髓 间充质基质/干细胞(MSCs)被认为是成骨细胞和 骨髓中的脂肪细胞，但对这两个谱系的承诺是相互排斥的。衰老会降低 骨髓间充质干细胞数量及其自我更新，有利于其向脂肪细胞分化 成骨细胞，导致骨质流失。通过siRNA筛选，我们发现组蛋白去甲基酶 KDM4B通过消除赖氨酸上三甲基化组蛋白H3在MSCs成骨分化中起关键作用 9(H3K9me3)。Kdm4b在衰老小鼠骨髓间充质干细胞中的表达显著下调 与年幼的老鼠相比。最近，我们在体内证明了KDM4B在MSCs中的敲除 通过减少骨形成和增加骨髓脂肪来加剧骨骼老化和骨质疏松 增加H3K9me3。为了探讨KDM4B的诱导或激活是否可以防止体内骨骼老化， 我们培育了过表达Kdm4b的敲门鼠。非常令人兴奋的是，我们发现Kdm4b的过度表达 显著延缓小鼠骨骼老化。出乎意料的是，我们的rna-seq分析显示， KDM4B在老年间充质干细胞中的表观遗传学促进自噬和抑制衰老基因信号 除了对细胞命运和干性的调节。越来越多的证据表明，自噬有助于维持 成体干细胞通过防止衰老而自我更新。自噬功能受损可削弱MSC 在骨骼老化过程中，茎和促进MSC的衰老和衰竭。当关键分子或信号 与自噬相关的途径已被阐明，自噬在骨骼老化中是如何表观遗传的 人们对监管知之甚少。根据我们令人兴奋的新发现，我们假设KDM4B 表观遗传学调控骨髓间充质干细胞在骨老化过程中的自噬、衰老和自我更新。我们建议 检测KDM4B在衰老小鼠中的诱导或激活是否能使骨髓间充质干细胞恢复活力并防止骨骼 通过使用遗传和小分子方法促进自噬和茎的衰老。新发现来自 我们的研究将对开发创新的治疗策略以预防 促进骨骼老化和骨质疏松症，以及促进MSC介导的骨再生。