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 该应用程序的长期目标是了解控制长期控制的表观遗传机制 口腔老化并探索靶向表观遗传因素是否可以帮助预防年龄相关 骨丢失。与年龄相关的骨质流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。它也代表了功能重建或牙齿，口服的再生的重大挑战 和颅面组织，例如牙科植入物，用于替代老年人的牙齿缺失。骨髓 间充质基质/干细胞（MSC）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。老化减少了 骨髓MSC编号及其自我更新，并以牺牲脂肪细胞为代价 成骨细胞，导致骨质流失。使用siRNA筛选，我们发现组蛋白脱甲基酶 KDM4B通过在赖氨酸的三甲基化组蛋白H3擦除MSC的成骨分化中起关键作用 9（H3K9me3）。从老化小鼠分离的MSC中，KDM4B的表达显着下调 与年轻小鼠相比。最近，我们证明了体内MSC中KDM4B的淘汰 通过减少骨形成并通过增加骨髓肥胖来加剧骨骼老化和骨质疏松症 增加H3K9me3。探索KDM4B的诱导或激活是否可以防止体内骨骼老化， 我们产生了过表达KDM4B的敲蛋白小鼠。非常令人兴奋的是，我们发现KDM4B的过表达 显着减弱了小鼠骨骼老化。出乎意料的是，我们的RNA-seq分析表明诱导 年龄MSC中的KDM4B表观遗传促进自噬并抑制衰老基因特征 补充细胞命运和茎的调节。越来越多的证据表明自噬有助于维持 成年干细胞的自我更新通过防止其衰老。自噬受损会减弱MSC 骨骼衰老中的茎和促进MSC衰老和精疲力尽。而关键分子或信号传导 与自噬相关的途径已经阐明，骨骼衰老的自噬是如何表观遗传的 受监管的理解很少。根据我们令人兴奋的新颖发现，我们假设KDM4B 表观遗传调节骨骼衰老中MSC的自噬，衰老和自我更新。我们建议 检查衰老小鼠中KDM4B的诱导或激活是否使MSC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干性来衰老。来自的新发现 我们的研究将对制定创新的治疗策略具有重要意义 骨骼老化和骨质疏松症以及促进MSC介导的骨再生。