Glutamate regulates gliosis of BMSCs to promote ENS regeneration through α-KG and H3K9/H3K27 demethylation

被引：10

作者：

Fan, Mengke ^{[1
]}

Shi, Huiying ^{[1
]}

Yao, Hailing ^{[1
]}

Wang, Weijun ^{[1
]}

Zhang, Yurui ^{[1
]}

Jiang, Chen ^{[1
]}

Lin, Rong ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Gastroenterol, Wuhan 430022, Peoples R China

来源：

STEM CELL RESEARCH & THERAPY | 2022年 / 13卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Bone marrow-derived mesenchymal stem cells (BMSCs); alpha-ketoglutarate (alpha-KG); Glud1 (glutamate dehydrogenase 1); Histone methylation; MESENCHYMAL STEM-CELLS; FIBRILLARY ACIDIC PROTEIN; EXCITOTOXICITY; NEURONS; METABOLISM; EXPRESSION; GDNF; BDNF; GFAP;

D O I：

10.1186/s13287-022-02936-7

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Background: There is a lack of effective therapies for enteric nervous system (ENS) injury. Our previous study showed that transplanted bone marrow-derived mesenchymal stem cells (BMSCs) play a"glia-like cells" role in initiating ENS regeneration in denervated mice. Cellular energy metabolism is an important factor in maintaining the biological characteristics of stem cells. However, how cellular energy metabolism regulates the fate of BMSCs in the ENS-injured microenvironment is unclear. Methods: The biological characteristics, energy metabolism, and histone methylation levels of BMSCs following ENS injury were determined. Then, glutamate dehydrogenase 1 (Glud1) which catalyzes the oxidative deamination of glutamate to alpha-KG was overexpressed (OE) in BMSCs. Further, OE-Glud1 BMSCs were targeted-transplanted into the ENS injury site of denervated mice to determine their effects on ENS regeneration. Results: In vitro, in the ENS-injured high-glutamate microenvironment, the ratio of alpha-ketoglutarate (alpha-KG) to succinate (P < 0.05), the histone demethylation level (P < 0.05), the protein expression of glial cell markers (P < 0.05), and the gene expression of Glud1 (P < 0.05) were significantly increased. And the binding of H3K9me3 to the GFAP, S100B, and GDNF promoter was enhanced (P < 0.05). Moreover, alpha-KG treatment increased the monomethylation and decreased the trimethylation on H3K9 (P < 0.01) and H3K27 (P < 0.05) in BMSCs and significantly upregulated the protein expression of glial cell markers (P < 0.01) , which was reversed by the alpha-KG competitive inhibitor D-2-hydroxyglutarate (P < 0.05). Besides, overexpression of Gludl in BMSCs exhibited increases in monomethylation and decreases in trimethylation on H3K9 (P < 0.05) and H3K27 (P < 0.05), and upregulated protein expression of glial cell markers (P < 0.01). In vivo, BMSCs overexpressing Glud1 had a strong promotion effect on ENS regeneration in denervated mice through H3K9/H3K27 demethylation (P < 0.05), and upregulating the expression of glial cell protein (P < 0.05). Conclusions: BMSCs overexpressing Glud1 promote the expression of glial cell markers and ENS remodeling in denervated mice through regulating intracellular alpha-KG and H3K9/H3K27 demethylation.

引用

页数：17

共 46 条

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