Regulating the cell differentiation trajectory of progenitor cells in adipose tissue fibrosis

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-08-06 DOI:10.1016/j.molmet.2025.102231

Li Zhang , Xinjiang Cai , Xiuju Wu , Zheng Jing , Yan Zhao , Yucheng Yao , Kristina I. Boström

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引用次数: 0

Abstract

Objective

Adipose fibrosis signifies pathological remodeling of white adipose tissue (WAT) associated with insulin resistance, diabetes, and cardiovascular disease. Matrix Gla protein (MGP) balances bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ) signaling but has an unclear role in WAT.

Methods

To study the role of MGP in WAT, we used mice with global or platelet-derived growth factor receptor α (Pdgfra)-Cre-mediated Mgp deletion in adipose progenitor cells (APCs) together with single cell RNA sequencing (scRNA-seq), characterization on adipose and fibrotic phenotypes, and BMP and TGFβ signaling studies.

Results

Our results showed that Mgp deletion promotes fibrosis and impairs adipogenesis in mice with global or Pdgfra-Cre-mediated Mgp deletion in APCs. ScRNA-seq showed two new adipose-derived stem cells (ASC) populations, ASC1 and ASC4, emerging after Mgp deletion. Trajectory analysis found that ASC1 and ASC4 were derived from ASC2, which normally undergo adipogenesis but instead had diverted to fibrogenic differentiation. All three ASCs expressed Pdgfra and dipeptidyl peptidase-4 (Dpp4). Inhibition of TGFβ signaling or DPP4 activity in mice with Pdgfra-Cre-mediated Mgp deletion reduced the size of the PDGFRα+; DPP4+ cell population and rescued the WAT from unwanted fibrosis.

Conclusions

MGP is essential for appropriate balance between adipogenic differentiation and fibroblast activation. Dysregulation of PDGFRα+; DPP4+ cells may signal early adipose fibrosis.

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调节脂肪组织纤维化中祖细胞的分化轨迹。

脂肪纤维化是指与胰岛素抵抗、糖尿病和心血管疾病相关的白色脂肪组织（WAT）的病理性重塑。基质玻璃蛋白（MGP）平衡骨形态发生蛋白（BMP）和转化生长因子β (TGFβ)信号，但在WAT中的作用尚不清楚。我们的研究表明，在脂肪祖细胞（APCs）中，由Pdgfra - cre介导的Mgp缺失小鼠中，Mgp基因缺失可促进纤维化并损害脂肪形成。单细胞RNA测序显示，Mgp缺失后出现了两个新的脂肪来源干细胞（ASC）群体，ASC1和ASC4。轨迹分析发现，ASC1和ASC4来源于ASC2，而ASC2通常经历脂肪形成，但却转向了纤维化分化。三种ASCs均表达Pdgfra和二肽基肽酶4 （Dpp4）。pdgfr - cre介导的Mgp缺失小鼠的信号研究，限制了TGFβ信号传导或DPP4活性，减少了PDGFRα+；DPP4+细胞群的大小，并使WAT免于不必要的纤维化。PDGFRα+、DPP4+细胞的失调可能是早期脂肪纤维化的信号。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.