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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该应用的长期目标是了解控制长期和长期的表观遗传机制。口面部骨老化，并探索针对表观遗传因素是否有助于预防与年龄相关的骨老化骨质流失。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。它还对牙齿、口腔、口腔等功能重建或再生提出了重大挑战。以及颅面组织，例如用于替换老年人缺失牙齿的牙种植体。骨髓间充质基质/干细胞（MSC）被认为是成骨细胞和成骨细胞的共同祖细胞。骨髓中的脂肪细胞，但这两个谱系的承诺是相互排斥的。老化会减少骨髓 MSC 数量及其自我更新，并有利于其分化为脂肪细胞，但代价是成骨细胞，导致骨质流失。通过 siRNA 筛选，我们发现组蛋白去甲基化酶 KDM4B 通过消除赖氨酸三甲基化组蛋白 H3 在 MSC 成骨分化中发挥关键作用 9（H3K9me3）。从衰老小鼠中分离的 MSC 中 Kdm4b 的表达显着下调与年轻小鼠相比。最近，我们证明在体内敲除 MSC 中的 KDM4B 通过减少骨形成和增加骨髓脂肪而加剧骨骼老化和骨质疏松症增加H3K9me3。为了探索 KDM4B 的诱导或激活是否可以预防体内骨骼衰老，我们生成了过度表达 Kdm4b 的敲入小鼠。非常令人兴奋的是，我们发现Kdm4b的过度表达显着减缓小鼠骨骼衰老。出乎意料的是，我们的 RNA-seq 分析表明，诱导衰老 MSC 中 KDM4B 的表观遗传促进自噬并抑制衰老基因特征除了细胞命运和干性的调节之外。越来越多的证据表明自噬有助于维持通过防止成体干细胞衰老来进行自我更新。自噬受损会减弱 MSC 干性并促进 MSC 衰老和骨骼衰老中的衰竭。虽然关键分子或信号传导与自噬相关的途径已被阐明，骨骼衰老中的自噬如何在表观遗传学上发挥作用监管的了解甚少。基于我们令人兴奋的新发现，我们假设 KDM4B 表观遗传调节骨骼衰老过程中 MSC 的自噬、衰老和自我更新。我们建议检查衰老小鼠中 KDM4B 的诱导或激活是否可以使 MSC 恢复活力并预防骨骼退化使用遗传和小分子方法促进自噬和干细胞衰老。新发现来自我们的研究将对开发预防疾病的创新治疗策略产生重要影响骨骼老化和骨质疏松症以及促进 MSC 介导的骨再生。