Mechanism of Matrix Gla Protein (MGP); Adipose Fibrosis

基质 Gla 蛋白 (MGP) 的作用机制；

• 批准号: 10670995
• 负责人: Kristina I Bostrom
• 金额: $ 58.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-24 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670995
• 关键词: Abnormal Endothelial Cell; Address; Adipose tissue; Area; BMP4; BMP7 gene; Binding Proteins; Blood Vessels; Bone Morphogenetic Proteins; Brown Fat; Cell Culture Techniques; Cell Separation; Cells; Chronic Disease; Complication; Development; Diabetes Mellitus; Disease; Dissection; Endothelial Cells; Endothelium; Excision; Extracellular Protein; F3 gene; Failure; Fatty acid glycerol esters; Fibrosis; Functional disorder; GDF10 gene; Gene Deletion; Gene Expression Profile; Gene Mutation; Goals; Hyperglycemia; Hyperlipidemia; ICAM1 gene; In Vitro; Inflammation; Inflammatory; Knockout Mice; Label; Ligands; Link; Location; MGP gene; Mediating; Mediator; Mesenchymal; Modeling; Molecular; Mus; Mutate; Myofibroblast; Normal tissue morphology; Obesity; Pathway interactions; Patients; Pattern; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Play; Population; Process; Protein Deficiency; Proteins; Regulation; Role; Signal Transduction; Sorting; Source; TGF-beta type I receptor; Testing; Thermogenesis; Tissues; Transforming Growth Factor beta; Vascularization; activin receptor-like kinase 1; bone loss; bone morphogenetic protein 4; bone morphogenetic protein receptors; experimental study; extracellular; growth differentiation factor 10; inhibitor; lipid biosynthesis; matrix Gla protein; multipotent cell; novel therapeutic intervention; prevent; progenitor; protein expression; receptor; repaired; single-cell RNA sequencing; stem cells

PROJECT SUMMARY: Adipose fibrosis is characterized by progressive stromal fibrosis that causes adipose dysfunction in obesity, diabetes, and inflammatory conditions. The sustained activation of unwanted myofibroblasts promotes progressive tissue changes with excessive amounts of altered fibrotic matrix. Although PDGFRα+ and CD9+ progenitor cells have been implicated, the cellular mechanisms remain unclear. Matrix Gla Protein (MGP) is an extracellular inhibitor of bone morphogenetic protein (BMP) 4, a mediator of endothelial cell (EC) inflammation. Loss of MGP triggers endothelial-mesenchymal transitions (EndMTs), a source of multipotent cells. We discovered that MGP is expressed in PDGFRα+ and CD9+ progenitor cells, and plays a limiting role in myofibroblast lineage in mice. By characterizing the adipose fibrosis in Mgp-knockout (KO) mice, integrating profiles from single-cell RNA sequencing (scRNA-seq) combined with cell sorting and culture, we propose to dissect the mechanism of MGP in adipose fibrosis. In preliminary studies, global Mgp deletion caused extensive adipose fibrosis in white adipose tissue (WAT) in mice. ScRNA-seq uncovered MGP expression in ECs and progenitors with projected trajectories towards myofibroblasts. Loss of Mgp enhanced abnormal ECs and cell populations with myofibrogenic potential, isolated by FACS. Mice with mutated Mgp lacking BMP- binding displayed fibrosis limited to perivascular areas, suggesting a structural role for MGP. EC-specific Mgp deletion largely mimicked the global fibrotic phenotype. We also found robust changes in brown adipose tissue (BAT) with excessive ECs, myofibroblasts, and abnormal thermogenesis. Potential mechanisms of differentiation involved BMP4/7, the BMP receptor ALK1, the TGFβ receptor ALK5. Our hypothesis is that loss of MGP causes transition and expansion of ECs and specific progenitors, followed by enhanced myofibroblast differentiation, in a two-step model. Aim 1 will elucidate the mechanism by which MGP regulates the transition of ECs and progenitors to myofibroblasts in WAT. We will characterize the Mgp- KO mouse as a new model of adipose fibrosis, using scRNA-seq, FACS and adipogenic cultures. We will assess EC contribution to myofibroblasts by lineage tracing using tdTomato-labeled ECs. In vitro, we will test profibrotic effects of BMP3b and BMP4/ALK1/ALK5 signaling. Aim 2 will determine whether loss of BMP- binding in MGP or endothelial deletion of MGP is sufficient to cause myofibroblasts transitions or a shift in the pattern of fibrosis. Comparisons of myofibroblast transition without BMP binding and endothelial deletion of Mgp allow us to deduce the anti-fibrotic of MGP and the relative importance of endothelial MGP. Aim 3 will characterize BAT after Mgp deletion. We will examine fibrotic and vascular phenotypes in Mgp-KO mice. We will identify MGP-expressing cell populations, their transcriptional profiles and cell trajectories, and determine how MGP helps direct brown adipogenesis by early BMP7. Our results may impact the field of obesity and obesity-related complications and lead to new therapeutic strategies that limit fibrosis in chronic disease.

项目总结： 脂肪纤维化的特征是进行性间质纤维化，导致肥胖患者脂肪功能障碍。 糖尿病和炎症状况。不需要的肌成纤维细胞的持续激活促进 进行性组织改变，伴有过量的纤维基质改变。虽然PDGFRα+和CD9+ 祖细胞已被牵连，但其细胞机制尚不清楚。基质GLA蛋白(MGP)是 一种骨形态发生蛋白4的细胞外抑制物，内皮细胞的介体 发炎。MGP缺失触发内皮细胞-间充质转化(EndMTs)，这是多潜能的来源之一 细胞。我们发现Mgp在PDGFRα+和CD9+祖细胞中表达，并发挥限制作用 在小鼠的肌成纤维细胞谱系中。通过表征MGP基因敲除(KO)小鼠的脂肪纤维化，整合 单细胞RNA测序图谱(scRNA-seq)结合细胞分选和培养，我们建议 剖析MGP在脂肪纤维化中的作用机制。在初步研究中，全球MGP缺失导致 小鼠白色脂肪组织广泛的脂肪纤维化(WAT)。ScRNA-seq发现Mgp在小鼠体内的表达 具有朝向肌成纤维细胞的投射轨迹的ECS和祖细胞。MGP增强的异常内皮细胞丢失 用流式细胞仪分离出具有肌纤维形成潜能的细胞群。缺乏BMP的MGP突变小鼠- 结合显示纤维化局限于血管周围区域，提示MGP的结构作用。EC特定的MGP 缺失在很大程度上模仿了全局性纤维化表型。我们还发现棕色脂肪组织有明显的变化。 (BAT)内皮细胞过多、肌成纤维细胞和异常产热。潜在的机制 分化涉及骨形态发生蛋白4/7、骨形态发生蛋白受体ALK1、转化生长因子β受体ALK5。 我们的假设是，MGP的丢失会导致内皮细胞和特定祖细胞的过渡和扩张，如下所述 通过增强肌成纤维细胞分化，在两步模型中。目标1将阐明 MGP调节WAT中内皮细胞和祖细胞向肌成纤维细胞的转化。我们将描述MGP的特征- KO小鼠作为一种新的脂肪纤维化模型，使用scRNA-seq、FACS和成脂培养。我们会 通过使用tdTomato标记的EC进行谱系追踪来评估EC对肌成纤维细胞的贡献。在体外，我们将测试 BMP3b和BMP4/ALK1/ALK5信号转导通路的促纤维化作用目标2将确定BMP的丢失是否- MGP的结合或MGP的内皮缺失足以引起肌成纤维细胞的转变或 纤维化的类型。无骨形态发生蛋白结合的肌成纤维细胞转化和血管内皮细胞缺失的比较 MGP使我们可以推断MGP的抗纤维化作用和内皮MGP的相对重要性。目标3将 MGP删除后的BAT特征。我们将研究MGP-KO小鼠的纤维化和血管表型。我们 将确定表达MGP的细胞群体、它们的转录图谱和细胞轨迹，并确定 MGP如何通过早期BMP7帮助引导棕色脂肪生成。我们的结果可能会影响肥胖症和 与肥胖相关的并发症，并导致限制慢性疾病纤维化的新治疗策略。

项目成果

Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.

• DOI: 10.1161/circresaha.110.219071
• 发表时间: 2010-08-20
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Yao Y;Bennett BJ;Wang X;Rosenfeld ME;Giachelli C;Lusis AJ;Boström KI
• 通讯作者: Boström KI

Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification.

• DOI: 10.1161/circresaha.115.306751
• 发表时间: 2015-10-09
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Yao J;Guihard PJ;Blazquez-Medela AM;Guo Y;Moon JH;Jumabay M;Boström KI;Yao Y
• 通讯作者: Yao Y

Cell Transitions Contribute to Glucocorticoid-Induced Bone Loss.

• DOI: 10.3390/cells12141810
• 发表时间: 2023-07-08
• 期刊: CELLS
• 影响因子: 6
• 作者: Qiao, Xiaojing;Wu, Xiuju;Zhao, Yan;Yang, Yang;Zhang, Li;Cai, Xinjiang;Ma, Jocelyn A. A.;Ji, Jaden;Lyons, Karen;Bostrom, Kristina I. I.;Yao, Yucheng
• 通讯作者: Yao, Yucheng

Activation of vascular bone morphogenetic protein signaling in diabetes mellitus.

• DOI: 10.1161/circresaha.110.236596
• 发表时间: 2011-02-18
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Boström KI;Jumabay M;Matveyenko A;Nicholas SB;Yao Y
• 通讯作者: Yao Y

Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice.

• DOI: 10.1016/j.jcmgh.2023.08.007
• 发表时间: 2023
• 期刊: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
• 影响因子: 7.2
• 作者: Hui, Simon T.;Gong, Lili;Swichkow, Chantle;Blencowe, Montgomery;Kaminska, Dorota;Diamante, Graciel;Pan, Calvin;Dalsania, Meet;French, Samuel W.;Magyar, Clara E.;Pajukanta, Paivi;Pihlajamaki, Jussi;Bostrom, Kristina I.;Yang, Xia;Lusis, Aldons J.
• 通讯作者: Lusis, Aldons J.