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IRX5通过抑制糖酵解促进人间充质干细胞的脂肪生成。

IRX5 promotes adipogenesis of hMSCs by repressing glycolysis.

作者信息

Jiang Bulin, Huang Liyuan, Tian Tian, Wu Hongling, Yao Hantao, Marmo Tyler, Song Fangfang, Huang Cui

机构信息

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, China.

Children's Hospital of Philadelphia, Philadelphia, PA, USA.

出版信息

Cell Death Discov. 2022 Apr 15;8(1):204. doi: 10.1038/s41420-022-00986-7.

DOI:10.1038/s41420-022-00986-7
PMID:35428362
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9012830/
Abstract

Iroquois homeobox transcription factor 5 (IRX5) plays a pivotal role in extramedullary adipogenesis, but little is known about the effects of IRX5 on adipogenesis of human bone marrow-derived mesenchymal stem cells (hMSCs). In this study, we aimed to determine the effect of IRX5 on hMSCs adipogenesis. By means of qPCR analysis, we determined that IRX5 expression was elevated during adipogenic commitment of hMSCs. The biologic role of IRX5 was further investigated by employing a gain/loss-of-function strategy using an in vitro lentivirus-based system. IRX5 overexpression promoted adipogenesis whereas IRX5 knockdown reduced the adipogenic phenotype. RNA-seq and metabolomics revealed that IRX5 overexpression repressed glycolysis. Dual-luciferase assay results showed that IRX5 overexpression transcriptionally activates peroxisome proliferator-activated receptor gamma coactivator (PGC-1α). Metformin and PGC-1α inhibitor reversed IRX5-induced adipogenesis and glycolytic inhibition. Collectively, IRX5 facilitates adipogenic differentiation of hMSCs by transcriptionally regulating PGC-1α and inhibiting glycolysis, revealing a potential target to control bone marrow-derived mesenchymal stem cells (BMSCs) fate decision and bone homeostasis.

摘要

易洛魁同源框转录因子5（IRX5）在髓外脂肪生成中起关键作用，但IRX5对人骨髓间充质干细胞（hMSCs）脂肪生成的影响知之甚少。在本研究中，我们旨在确定IRX5对hMSCs脂肪生成的影响。通过qPCR分析，我们确定在hMSCs脂肪生成过程中IRX5表达升高。利用基于体外慢病毒系统的功能获得/丧失策略进一步研究了IRX5的生物学作用。IRX5过表达促进脂肪生成，而IRX5敲低则降低脂肪生成表型。RNA测序和代谢组学显示，IRX5过表达抑制糖酵解。双荧光素酶测定结果表明，IRX5过表达转录激活过氧化物酶体增殖物激活受体γ共激活因子（PGC-1α）。二甲双胍和PGC-1α抑制剂可逆转IRX5诱导的脂肪生成和糖酵解抑制。总之，IRX5通过转录调节PGC-1α和抑制糖酵解促进hMSCs的脂肪生成分化，揭示了一个控制骨髓间充质干细胞（BMSCs）命运决定和骨稳态的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/5185dcdd6f3b/41420_2022_986_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/4c84c602e20f/41420_2022_986_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/daea52b8c4a7/41420_2022_986_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/005164bf6163/41420_2022_986_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/7f39adc78ea0/41420_2022_986_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/311a2b821fe9/41420_2022_986_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/cc37493edae8/41420_2022_986_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/992786092902/41420_2022_986_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/5185dcdd6f3b/41420_2022_986_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/4c84c602e20f/41420_2022_986_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/daea52b8c4a7/41420_2022_986_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/005164bf6163/41420_2022_986_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/7f39adc78ea0/41420_2022_986_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/311a2b821fe9/41420_2022_986_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/cc37493edae8/41420_2022_986_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/992786092902/41420_2022_986_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e5a/9012830/5185dcdd6f3b/41420_2022_986_Fig8_HTML.jpg

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