Glutamine-αKG axis affects dentin regeneration and regulates osteo/odontogenic differentiation of mesenchymal adult stem cells via IGF2 m6A modification

被引：1
作者：
Tian, Qinglu [1 ]
Gao, Shiqi [3 ,4 ]
Li, Siying [1 ]
Wan, Mian [2 ]
Zhou, Xin [1 ]
Du, Wei [2 ]
Zhou, Xuedong [2 ]
Zheng, Liwei [1 ]
Zhou, Yachuan [2 ]
机构：
[1] Sichuan Univ, Natl Clin Res Ctr Oral Dis, West China Hosp Stomatol, State Key Lab Oral Dis,Dept Pediat Dent, Chengdu 610041, Sichuan, Peoples R China
[2] Sichuan Univ, Natl Clin Res Ctr Oral Dis, West China Hosp Stomatol, State Key Lab Oral Dis,Dept Cariol & Endodont, Chengdu 610041, Sichuan, Peoples R China
[3] Guangzhou Med Univ, Sch & Hosp Stomatol, Guangdong Engn Res Ctr Oral Restorat & Reconstruct, Guangzhou, Peoples R China
[4] Guangzhou Med Univ, Guangzhou Key Lab Basic & Appl Res Oral Regenerat, Guangzhou, Peoples R China
来源：
STEM CELL RESEARCH & THERAPY | 2024年 / 15卷 / 01期
基金：
中国国家自然科学基金;
关键词：
ASCs; Glutamine-alpha KG Axis; Mesenchymal stem cells; Dentin regeneration; IGF2; Epigenetic; GENE-EXPRESSION; OSTEOGENIC DIFFERENTIATION; RNA MODIFICATIONS; METABOLISM;
D O I：
10.1186/s13287-024-04092-6
中图分类号：
Q813 [细胞工程];
学科分类号：
摘要：
BackgroundMulti-lineage differentiation of mesenchymal adult stem cells (m-ASCs) is crucial for tissue regeneration and accompanied with metabolism reprogramming, among which dental-pulp-derived m-ASCs has obvious advantage of easy accessibility. Stem cell fate determination and differentiation are closely related to metabolism status in cell microenvironment, which could actively interact with epigenetic modification. In recent years, glutamine-alpha-ketoglutarate (alpha KG) axis was proved to be related to aging, tumorigenesis, osteogenesis etc., while its role in m-ASCs still lack adequate research evidence.MethodsWe employed metabolomic analysis to explore the change pattern of metabolites during dental-pulp-derived m-ASCs differentiation. A murine incisor clipping model was established to investigate the influence of alpha KG on dental tissue repairment. shRNA technique was used to knockdown the expression of related key enzyme-dehydrogenase 1(GLUD1). RNA-seq, m6A evaluation and MeRIP-qPCR were used to dig into the underlying epigenetic mechanism.ResultsHere we found that the glutamine-alpha KG axis displayed an increased tendency along with the osteo/odontogenic differentiation of dental-pulp-derived m-ASCs, same as expression pattern of GLUD1. Further, the key metabolite alpha KG was found able to accelerate the repairment of clipped mice incisor and promote dentin formation. Exogenous DM-alpha KG was proved able to promote osteo/odontogenic differentiation of dental-pulp-derived m-ASCs, while the inhibition of glutamine-derived alpha KG level via GLUD1 knockdown had the opposite effect. Under the circumstance of GLUD1 knockdown, extracellular matrix (ECM) function and PI3k-Akt signaling pathway was screened out to be widely involved in the process with insulin-like growth factor 2 (IGF2) participation via RNA-seq. Inhibition of glutamine-alpha KG axis may affect IGF2 translation efficiency via m6A methylation and can be significantly rescued by alpha KG supplementation.ConclusionOur findings indicate that glutamine-alpha KG axis may epigenetically promote osteo/odontogenic differentiation of dental-pulp-derived m-ASCs and dentin regeneration, which provide a new research vision of potential dental tissue repairment therapy method or metabolite-based drug research.
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页数：17
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共 59 条
  • [1] Zhao J., Du W., Guo D., Wang S., Du W., Mechanical signaling in dental pulp stem cells, Front Biosci (Landmark Ed), 28, 10, (2023)
  • [2] Nagata M., Ono N., Ono W., Unveiling diversity of stem cells in dental pulp and apical papilla using mouse genetic models: a literature review, Cell Tissue Res, 383, 2, pp. 603-616, (2021)
  • [3] Ferro F., Spelat R., Baheney C.S., Dental pulp stem cell (DPSC) isolation, characterization, and differentiation, Methods Mol Biol, 1210, pp. 91-115, (2014)
  • [4] Tsutsui T.W., Dental pulp stem cells: advances to applications, Stem Cells Cloning, 13, pp. 33-42, (2020)
  • [5] Yang X., Li L., Xiao L., Zhang D., Recycle the dental fairy's package: overview of dental pulp stem cells, Stem Cell Res Ther, 9, 1, (2018)
  • [6] Luo N., Deng Y.W., Wen J., Xu X.C., Jiang R.X., Zhan J.Y., Et al., Wnt3a-loaded hydroxyapatite Nanowire@Mesoporous silica core-shell nanocomposite promotes the regeneration of dentin-pulp complex via angiogenesis, oxidative stress resistance, and odontogenic induction of stem cells, Adv Healthc Mater, 12, 22, (2023)
  • [7] Han J., Kim D.S., Jang H., Kim H.R., Kang H.W., Bioprinting of three-dimensional dentin-pulp complex with local differentiation of human dental pulp stem cells, J Tissue Eng, 10, (2019)
  • [8] Xiao D., Zeng L., Yao K., Kong X., Wu G., Yin Y., The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications, Amino Acids, 48, 9, pp. 2067-2080, (2016)
  • [9] Liu S., He L., Yao K., The antioxidative function of alpha-ketoglutarate and its applications, Biomed Res Int, 2018, (2018)
  • [10] Wu N., Yang M., Gaur U., Xu H., Yao Y., Li D., Alpha-ketoglutarate: physiological functions and applications, Biomol Ther (Seoul), 24, 1, pp. 1-8, (2016)
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