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On-line Access: 2022-12-15

Received: 2022-03-07

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Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.12 P.989-1001


Macrophage migration inhibitory factor protects bone marrow mesenchymal stem cells from hypoxia/ischemia-induced apoptosis by regulating lncRNA MEG3

Author(s):  Zhibiao BAI, Kai HU, Jiahuan YU, Yizhe SHEN, Chun CHEN

Affiliation(s):  First Clinical Medicine Institute, Wenzhou Medical University, Wenzhou 325006, China; more

Corresponding email(s):   chenchunkk@163.com

Key Words:  Macrophage migration inhibitory factor (MIF), Long noncoding RNA (lncRNA), Maternally expressed gene 3 (MEG3), Bone marrow mesenchymal stem cells (BMSCs), β, -Catenin, Apoptosis

Zhibiao BAI, Kai HU, Jiahuan YU, Yizhe SHEN, Chun CHEN. Macrophage migration inhibitory factor protects bone marrow mesenchymal stem cells from hypoxia/ischemia-induced apoptosis by regulating lncRNA MEG3[J]. Journal of Zhejiang University Science B, 2022, 23(12): 989-1001.

@article{title="Macrophage migration inhibitory factor protects bone marrow mesenchymal stem cells from hypoxia/ischemia-induced apoptosis by regulating lncRNA MEG3",
author="Zhibiao BAI, Kai HU, Jiahuan YU, Yizhe SHEN, Chun CHEN",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Macrophage migration inhibitory factor protects bone marrow mesenchymal stem cells from hypoxia/ischemia-induced apoptosis by regulating lncRNA MEG3
%A Zhibiao BAI
%A Kai HU
%A Jiahuan YU
%A Yizhe SHEN
%A Chun CHEN
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 12
%P 989-1001
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200110

T1 - Macrophage migration inhibitory factor protects bone marrow mesenchymal stem cells from hypoxia/ischemia-induced apoptosis by regulating lncRNA MEG3
A1 - Zhibiao BAI
A1 - Kai HU
A1 - Jiahuan YU
A1 - Yizhe SHEN
A1 - Chun CHEN
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 12
SP - 989
EP - 1001
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200110

ObjectiveThis research was performed to explore the effect of macrophage migration inhibitory factor (MIF) on the apoptosis of bone marrow mesenchymal stem cells (BMSCs) in ischemia and hypoxia environments.
MethodsThe cell viability of BMSCs incubated under hypoxia/ischemia (H/I) conditions with or without pretreatment with MIF or triglycidyl isocyanurate (TGIC) was detected using cell counting kit-8 (CCK-8) analysis. Plasmids containing long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) or β;-Catenin small interfering RNA (siRNA) were used to overexpress or downregulate the corresponding gene, and the p53 signaling pathway was activated by pretreatment with TGIC. The influences of MIF, overexpression of lncRNA MEG3, activation of the p53 signaling pathway, and silencing of β;-Catenin on H/I-induced apoptosis of BMSCs were revealed by western blotting, flow cytometry, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining.
ResultsFrom the results of CCK-8 assay, western blotting, and flow cytometry, pretreatment with MIF significantly decreased the H/I-induced apoptosis of BMSCs. This effect was inhibited when lncRNA MEG3 was overexpressed by plasmids containing MEG3. The p53 signaling pathway was activated by TGIC, and β;-Catenin was silenced by siRNA. From western blot results, the expression levels of β;-Catenin in the nucleus and phosphorylated p53 (p-p53) were downregulated and upregulated, respectively, when the lncRNA MEG3 was overexpressed. Through flow cytometry, MIF was also shown to significantly alleviate the increased reactive oxygen species (ROS) level of BMSCs caused by H/I.
ConclusionsIn summary, we conclude that MIF protected BMSCs from H/I-induced apoptosis by downregulating the lncRNA MEG3/p53 signaling pathway, activating the Wnt/β;-Catenin signaling pathway, and decreasing ROS levels.

巨噬细胞迁移抑制因子通过调控长链非编码RNA MEG3保护骨髓间充质干细胞免受缺氧/缺血诱导的细胞凋亡

创新点:(1)阐明了长链非编码RNA(lncRNA)MEG3在H/I诱导的小鼠BMSCs凋亡中的作用;(2)发现MIF可以通过调节lncRNA MEG3/p53信号通路缓解H/I介导的BMSCs凋亡;(3)MIF的细胞保护作用还与激活Wnt/β-连环蛋白(β-catenin)信号通路和降低活性氧(ROS)水平相关。
结果:CCK-8、蛋白质印迹法和流式细胞术检测结果显示:MIF预处理可显著降低细胞内的ROS水平,改善H/I诱导的BMSCs凋亡;LncRNA MEG3过表达时细胞核内β-catenin的含量明显减少,而p-p53的表达上调;当p53信号通路被激活,β-catenin的表达被抑制时,MIF对H/I环境下BMSCs的保护作用明显减弱。
结论:MIF通过下调lncRNA MEG3/p53信号通路、激活Wnt/β-catenin信号通路和降低ROS水平来保护BMSCs免受H/I诱导的凋亡。

关键词:巨噬细胞迁移抑制因子;长链非编码RNA MEG3;骨髓间充质干细胞;β-连环蛋白(β-catenin);凋亡

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]BöttcherA, BüttnerM, TritschlerS, et al., 2021. Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and paneth cell fates. Nat Cell Biol, 23(1):23-31.

[2]CalandraT, BernhagenJ, MitchellRA, et al., 1994. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med, 179(6):1895-1902.

[3]ChenRP, HuangZL, LiuLX, et al., 2016. Involvement of endoplasmic reticulum stress and p53 in lncRNA MEG3-induced human hepatoma HepG2 cell apoptosis. Oncol Rep, 36(3):1649-1657.

[4]DuR, LiJ, WuYT, 2020. Expression of SFRP1 and MIF in elderly patients with severe periodontitis and its correlation with cognitive function. Shanghai J Stomatol, 29(1):97-101 (in Chinese).

[5]FanLH, ZhangC, YuZF, et al., 2015. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and osteogenesis in rabbit femoral head osteonecrosis. Bone, 81:544-553.

[6]FukayaR, OhtaS, YaguchiT, et al., 2016. MIF maintains the tumorigenic capacity of brain tumor-initiating cells by directly inhibiting p53. Cancer Res, 76(9):2813-2823.

[7]GeorgeG, LaneJM, 2022. Osteonecrosis of the femoral head. J Am Acad Orthop Surg Glob Res Rev, 6(5):e21.00176.

[8]HinesJT, JoWL, CuiQJ, et al., 2021. Osteonecrosis of the femoral head: an updated review of arco on pathogenesis, staging and treatment. J Korean Med Sci, 36(24):e177.

[9]HouM, CuiJJ, LiuJJ, et al., 2014. Angiopoietin-like 4 confers resistance to hypoxia/serum deprivation-induced apoptosis through PI3K/Akt and ERK1/2 signaling pathways in mesenchymal stem cells. PLoS ONE, 9(1):e85808.

[10]JarrouxJ, MorillonA, PinskayaM, 2017. History, discovery, and classification of lncRNAs. In: Rao MRS (Ed.), Long Non Coding RNA Biology. Springer, Singapore, p.1-46.

[11]JiaoDL, ZhengA, LiuY, et al., 2021. Bidirectional differentiation of BMSCs induced by a biomimetic procallus based on a gelatin-reduced graphene oxide reinforced hydrogel for rapid bone regeneration. Bioact Mater, 6(7):‍2011-2028.

[12]JungC, KimMH, KimYY, et al., 2021. Determining the optimal administration conditions under which MIF exerts neuroprotective effects by inducing BDNF expression and inhibiting apoptosis in an in vitro stroke model. Brain Sci, 11(2):280.

[13]KimSH, WangWH, WangJP, et al., 2018. Teroxirone suppresses growth and motility of human hepatocellular carcinoma cells. Biomed Pharmacother, 99:997-1008.

[14]MaJ, LiTF, HanXW, et al., 2019. Downregulated MEG3 contributes to tumour progression and poor prognosis in oesophagal squamous cell carcinoma by interacting with miR-4261, downregulating DKK2 and activating the Wnt/β-catenin signalling. Artif Cells Nanomed Biotechnol, 47(1):1513-1523.

[15]QiuGZ, TianW, FuHT, et al., 2016. Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem Biophys Res Commun, 471(1):135-141.

[16]SarkarD, LeungEY, BaguleyBC, et al., 2015. Epigenetic regu

[17]lation in human melanoma: past and future. Epigenetics, 10(2):103-121.

[18]SongHL, ShenQ, HuS, et al., 2020. The role of macrophage migration inhibitory factor in promoting benign prostatic hyperplasia epithelial cell growth by modulating COX-2 and P53 signaling. Biol Open, 9(11):bio053447.

[19]UrodaT, AnastasakouE, RossiA, et al., 2019. Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway. Mol Cell, 75(5):982-995.e9.

[20]WajnerM, VargasCR, AmaralAU, 2020. Disruption of mitochondrial functions and oxidative stress contribute to neurologic dysfunction in organic acidurias. Arch Biochem Biophys, 696:108646.

[21]WirtzTH, SaalA, BergmannI, et al., 2021. Macrophage migration inhibitory factor exerts pro-proliferative and anti-apoptotic effects via CD74 in murine hepatocellular carcinoma. Br J Pharmacol, 178(22):4452-4467.

[22]XiaWZ, HouM, 2016. Macrophage migration inhibitory factor induces autophagy to resist hypoxia/serum deprivation-induced apoptosis via the AMP-activated protein kinase/mammalian target of rapamycin signaling pathway. Mol Med Rep, 13(3):2619-2626.

[23]XiaWZ, XieCY, JiangMM, et al., 2015. Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor. Mol Cell Biochem, 404(1-2):11-24.

[24]XiaWZ, ZhuangL, HouM, 2018. Role of lincRNA-p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation-induced apoptosis in mesenchymal stem cells. Int J Mol Med, 42(4):2175-2184.

[25]XiaY, HeZC, LiuB, et al., 2015. Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway. Mol Med Rep, 12(3):4530-4537.

[26]XieB, QiaoML, XuanJL, 2021. LncRNA MEG3 downregulation relieves intracerebral hemorrhage by inhibiting oxidative stress and inflammation in an miR-181b-dependent manner. Med Sci Monit, 27:e929435.

[27]XuHX, WangCQ, LiuC, et al., 2021. Cotransplantation of mesenchymal stem cells and endothelial progenitor cells for treating steroid-induced osteonecrosis of the femoral head. Stem Cells Transl Med, 10(5):781-796.

[28]XuJH, SuCJ, ZhaoFL, et al., 2018. Paclitaxel promotes lung cancer cell apoptosis via MEG3-P53 pathway activation. Biochem Biophys Res Commun, 504(1):123-128.

[29]YanHL, YuanJP, GaoLK, et al., 2016. Long noncoding RNA MEG3 activation of p53 mediates ischemic neuronal death in stroke. Neuroscience, 337:191-199.

[30]YoshihisaY, RehmanMU, KondoT, et al., 2016. Role of macrophage migration inhibitory factor in heat-induced apoptosis in keratinocytes. FASEB J, 30(11):3870-3877.

[31]YuH, LiSB, 2020. Role of LINC00152 in non-small cell lung cancer. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(3):179-191.

[32]YuanL, ZhangPQ, LuYM, et al., 2022. LINC00662 promotes proliferation and invasion and inhibits apoptosis of glioma cells through miR-483-3p/SOX3 axis. Appl Biochem Biotechnol, 194(7):2857-2871.

[33]ZengY, ChenC, LiuW, et al., 2015. Injectable microcryogels reinforced alginate encapsulation of mesenchymal stromal cells for leak-proof delivery and alleviation of canine disc degeneration. Biomaterials, 59:53-65.

[34]ZhangY, WuJ, JingH, et al., 2019. Long noncoding RNA MEG3 inhibits breast cancer growth via upregulating endoplasmic reticulum stress and activating NF-κB and p53. J Cell Biochem, 120(4):6789-6797.

[35]ZhangYL, ZhuWW, HeHW, et al., 2019. Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair. Aging, 11(24):12641-12660.

[36]ZhaoQ, LiuXR, YuCY, et al., 2022. Macrophages and bone marrow-derived mesenchymal stem cells work in concert to promote fracture healing: a brief review. DNA Cell Biol, 41(3):276-284.

[37]ZhuWQ, ChenJH, CongXF, et al., 2006. Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells, 24(2):416-425.

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