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.

项目概要： 脂肪纤维化的特征在于进行性基质纤维化，其导致肥胖症中的脂肪功能障碍， 糖尿病和炎症。不需要的肌成纤维细胞的持续激活促进了 进行性组织变化，伴有过量的改变的纤维化基质。虽然PDGFRα+和CD 9 + 虽然已经涉及祖细胞，但细胞机制仍不清楚。基质Gla蛋白（MGP） 骨形态发生蛋白（BMP）4的细胞外抑制剂，内皮细胞（EC）的介质 炎症MGP的缺失触发内皮-间充质转化（EndMT），这是多能性血管生成的来源。 细胞我们发现，MGP在PDGFRα+和CD 9+祖细胞中表达，并起限制作用， 在小鼠肌成纤维细胞谱系中。通过表征Mgp敲除（KO）小鼠中的脂肪纤维化，整合 从单细胞RNA测序（scRNA-seq）与细胞分选和培养相结合的概况，我们建议 探讨MGP在脂肪纤维化中的作用机制。在初步研究中，全局Mgp缺失导致 小鼠白色脂肪组织（WAT）中广泛的脂肪纤维化。ScRNA-seq揭示了MGP表达， 具有朝向肌成纤维细胞的投射轨迹的EC和祖细胞。Mgp缺失增强异常EC 和通过FACS分离的具有肌纤维化潜能的细胞群。具有突变的Mgp缺乏BMP的小鼠- 结合显示纤维化局限于血管周围区域，表明MGP的结构作用。EC特异性Mgp 缺失在很大程度上模拟了整体纤维化表型。我们还发现棕色脂肪组织 (BAT)有过多的内皮细胞肌成纤维细胞和异常产热的潜在机制 分化涉及BMP 4/7、BMP受体ALK 1、TGFβ受体ALK 5。 我们的假设是，MGP的缺失导致EC和特定祖细胞的转变和扩增， 通过两步模型增强肌成纤维细胞分化。目标1将阐明 在WAT中，MGP调节EC和祖细胞向肌成纤维细胞的转变。我们将描述Mgp- KO小鼠作为脂肪纤维化的新模型，使用scRNA-seq、FACS和脂肪形成培养物。我们将 使用tdTomato标记的EC通过谱系追踪评估EC对肌成纤维细胞的贡献。在体外，我们将测试 BMP 3b和BMP 4/ALK 1/ALK 5信号传导的促纤维化作用。目标2将确定BMP的丢失是否- MGP中的结合或MGP的内皮缺失足以引起肌成纤维细胞的转变或肌成纤维细胞的移位。 纤维化的模式。无BMP结合和内皮缺失的肌成纤维细胞转化的比较 MGP的抗纤维化作用及内皮细胞MGP的相对重要性。目标3将 在Mgp缺失后表征BAT。我们将检查Mgp-KO小鼠的纤维化和血管表型。我们 将鉴定表达MGP的细胞群，它们的转录谱和细胞轨迹，并确定 MGP如何通过早期BMP 7帮助指导棕色脂肪形成。我们的研究结果可能会影响肥胖领域， 肥胖相关的并发症，并导致新的治疗策略，限制慢性疾病的纤维化。

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.