Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

Open Access 01-12-2020 | Hypoxic-Ischemic Brain Injury | Research

RETRACTED ARTICLE:Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway

Authors: Kun Hou, Guichen Li, Jinchuan Zhao, Baofeng Xu, Yang Zhang, Jinlu Yu, Kan Xu

Published in: Journal of Neuroinflammation | Issue 1/2020

Login to get access

Abstract

Background

Mesenchymal stem cells (MSCs) are suspected to exert neuroprotective effects in brain injury, in part through the secretion of extracellular vesicles like exosomes containing bioactive compounds. We now investigate the mechanism by which bone marrow MSCs (BMSCs)-derived exosomes harboring the small non-coding RNA miR-29b-3p protect against hypoxic-ischemic brain injury in rats.

Methods

We established a rat model of middle cerebral artery occlusion (MCAO) and primary cortical neuron or brain microvascular endothelial cell (BMEC) models of oxygen and glucose deprivation (OGD). Exosomes were isolated from the culture medium of BMSCs. We treated the MCAO rats with BMSC-derived exosomes in vivo, and likewise the OGD-treated neurons and BMECs in vitro. We then measured apoptosis- and angiogenesis-related features using TUNEL and CD31 immunohistochemical staining and in vitro Matrigel angiogenesis assays.

Results

The dual luciferase reporter gene assay showed that miR-29b-3p targeted the protein phosphatase and tensin homolog (PTEN). miR-29b-3p was downregulated and PTEN was upregulated in the brain of MCAO rats and in OGD-treated cultured neurons. MCAO rats and OGD-treated neurons showed promoted apoptosis and decreased angiogenesis, but overexpression of miR-29b-3p or silencing of PTEN could reverse these alterations. Furthermore, miR-29b-3p could negatively regulate PTEN and activate the Akt signaling pathway. BMSCs-derived exosomes also exerted protective effects against apoptosis of OGD neurons and cell apoptosis in the brain samples from MCAO rats, where we also observed promotion of angiogenesis.

Conclusion

BMSC-derived exosomal miR-29b-3p ameliorates ischemic brain injury by promoting angiogenesis and suppressing neuronal apoptosis, a finding which may be of great significance in the treatment of hypoxic-ischemic brain injury.
Appendix
Available only for authorised users
Literature
1.
Saeed E, Ali R, Jalal-ud-din M, Saeed A, Jadoon RJ, Moiz M. Hypercholesterolemia in patients of ischemic stroke. J Ayub Med Coll Abbottabad. 2015;27:637–9.PubMed
2.
Song H, Zhou H, Qu Z, Hou J, Chen W, Cai W, Cheng Q, Chuang DY, Chen S, Li S, Li J, Cheng J, Greenlief CM, Lu Y, Simonyi A, Sun GY, Wu C, Cui J, Gu Z. From Analysis of Ischemic Mouse Brain Proteome to Identification of Human Serum Clusterin as a Potential Biomarker for Severity of Acute Ischemic Stroke. Transl Stroke Res. 2019;10(5):546–56.
3.
4.
Wang Y, Luo J, Li SY. Nano-Curcumin simultaneously protects the blood-brain barrier and reduces M1 microglial activation during cerebral ischemia-reperfusion injury. ACS Appl Mater Interfaces. 2019;11:3763–70.PubMed
5.
Zerna C, Thomalla G, Campbell BCV, Rha JH, Hill MD. Current practice and future directions in the diagnosis and acute treatment of ischaemic stroke. Lancet. 2018;392:1247–56.PubMed
6.
Won SJ, Kim DY, Gwag BJ. Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol. 2002;35:67–86.PubMed
7.
Ruan L, Wang B, ZhuGe Q, Jin K. Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res. 1623;2015:166–73.
8.
Lee JA, Kim BI, Jo CH, Choi CW, Kim EK, Kim HS, Yoon KS, Choi JH. Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. Pediatr Res. 2010;67:42–6.PubMed
9.
Ward MR, Abadeh A, Connelly KA. Concise review: rational use of mesenchymal stem cells in the treatment of ischemic heart disease. Stem Cells Transl Med. 2018;7:543–50.PubMedPubMedCentral
10.
Zhang D, Lee H, Zhu Z, Minhas JK, Jin Y. Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol. 2017;312:L110–L21.PubMed
11.
Zhu CG, Liu YX, Wang H, Wang BP, Qu HQ, Wang BL, Zhu M. Active form of vitamin D ameliorates non-alcoholic fatty liver disease by alleviating oxidative stress in a high-fat diet rat model. Endocr J. 2017;64:663–73.PubMed
12.
Birch D, Britt BC, Dukes SC, Kessler JA, Dizon ML. MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia. Pediatr Res. 2014;76:334–40.PubMedPubMedCentral
13.
Majdi A, Mahmoudi J, Sadigh-Eteghad S, Farhoudi M, Shotorbani SS. The interplay of microRNAs and post-ischemic glutamate excitotoxicity: an emergent research field in stroke medicine. Neurol Sci. 2016;37:1765–71.PubMed
14.
Widlansky ME, Jensen DM, Wang J, Liu Y, Geurts AM, Kriegel AJ, Liu P, Ying R, Zhang G, Casati M, Chu C, Malik M, Branum A, Tanner MJ, Tyagi S, Usa K, Liang M. miR-29 contributes to normal endothelial function and can restore it in cardiometabolic disorders. EMBO Mol Med. 2018;10(3).
15.
Dai Y, Mao Z, Han X, Xu Y, Xu L, Yin L, Qi Y, Peng J. MicroRNA-29b-3p reduces intestinal ischaemia/reperfusion injury via targeting of TNF receptor-associated factor 3. Br J Pharmacol. 2019;176:3264–78.PubMedPubMedCentral
16.
Garcia-Junco-Clemente P, Golshani P. PTEN: a master regulator of neuronal structure, function, and plasticity. Commun Integr Biol. 2014;7:e28358.PubMedPubMedCentral
17.
Qu L, Gao Y, Sun H, Wang H, Liu X, Sun D. Role of PTEN-Akt-CREB signaling pathway in nervous system impairment of rats with chronic Arsenite exposure. Biol Trace Elem Res. 2016;170:366–72.PubMed
18.
Hung PL, Hsu MH, Yu HR, Wu KLH, Wang FS. Thyroxin Protects White Matter from Hypoxic-Ischemic Insult in the Immature Sprague−Dawley Rat Brain by Regulating Periventricular White Matter and Cortex BDNF and CREB Pathways. Int J Mol Sci. 2018;19(9).
19.
Huang W, Shao M, Liu H, Chen J, Hu J, Zhu L, Liu F, Wang D, Zou Y, Xiong Y, Wang X. Fibroblast growth factor 21 enhances angiogenesis and wound healing of human brain microvascular endothelial cells by activating PPARgamma. J Pharmacol Sci. 2019;140:120–7.PubMed
20.
Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20:84–91.PubMed
21.
Zhang G, Ge M, Han Z, Wang S, Yin J, Peng L, Xu F, Zhang Q, Dai Z, Xie L, Li Y, Si J, Ma K. Wnt/beta-catenin signaling pathway contributes to isoflurane postconditioning against cerebral ischemia-reperfusion injury and is possibly related to the transforming growth factorbeta1/Smad3 signaling pathway. Biomed Pharmacother. 2019;110:420–30.PubMed
22.
Jiang M, Wang H, Jin M, Yang X, Ji H, Jiang Y, Zhang H, Wu F, Wu G, Lai X, et al. Exosomes from MiR-30d-5p-ADSCs reverse acute ischemic stroke-induced, autophagy-mediated brain injury by promoting M2 microglial/macrophage polarization. Cell Physiol Biochem. 2018;47:864–78.PubMed
23.
Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17:472–6.PubMed
24.
Huang X, Ding J, Li Y, Liu W, Ji J, Wang H, Wang X. Exosomes derived from PEDF modified adipose-derived mesenchymal stem cells ameliorate cerebral ischemia-reperfusion injury by regulation of autophagy and apoptosis. Exp Cell Res. 2018;371:269–77.PubMed
25.
Yavin Z, Yavin E. Survival and maturation of cerebral neurons on poly(L-lysine) surfaces in the absence of serum. Dev Biol. 1980;75:454–9.PubMed
26.
Qin AP, Liu CF, Qin YY, Hong LZ, Xu M, Yang L, Liu J, Qin ZH, Zhang HL. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy. 2010;6:738–53.PubMed
27.
Goldberg MP, Choi DW. Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci. 1993;13:3510–24.PubMedPubMedCentral
28.
Wang L, Pei S, Han L, Guo B, Li Y, Duan R, Yao Y, Xue B, Chen X, Jia Y. Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFkappaB P65 subunit in spinal cord injury. Cell Physiol Biochem. 2018;50:1535–59.PubMed
29.
Ayuk SM, Abrahamse H, Houreld NN. The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro. J Photochem Photobiol B. 2016;161:368–74.PubMed
30.
Weidner N. Tumor angiogenesis: review of current applications in tumor prognostication. Semin Diagn Pathol. 1993;10:302–13.PubMed
31.
Dai Y, Mao Z, Han X, Xu Y, Xu L, Yin L, Qi Y, Peng J. MicroRNA-29b-3p reduces intestinal ischemia/reperfusion injury via targeting of TRAF3. Br J Pharmacol. 2019;176(17):3264–78.PubMedPubMedCentral
32.
Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noel D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep. 2017;7:16214.PubMedPubMedCentral
33.
Thomi G, Surbek D, Haesler V, Joerger-Messerli M, Schoeberlein A. Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury. Stem Cell Res Ther. 2019;10:105.PubMedPubMedCentral
34.
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008;8:187–98.PubMed
35.
Herz J, Koster C, Reinboth BS, Dzietko M, Hansen W, Sabir H, van Velthoven C, Bendix I, Felderhoff-Muser U. Interaction between hypothermia and delayed mesenchymal stem cell therapy in neonatal hypoxic-ischemic brain injury. Brain Behav Immun. 2018;70:118–30.PubMed
36.
Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, Yu B, Chen X, Li X, Zhang X. Effects of Mesenchymal stem cell-derived exosomes on experimental autoimmune uveitis. Sci Rep. 2017;7:4323.PubMedPubMedCentral
37.
Shamili FH, Bayegi HR, Salmasi Z, Sadri K, Mahmoudi M, Kalantari M, Ramezani M, Abnous K. Exosomes derived from TRAIL-engineered mesenchymal stem cells with effective anti-tumor activity in a mouse melanoma model. Int J Pharm. 2018;549:218–29.PubMed
38.
Cui H, Yang L. Analysis of microRNA expression detected by microarray of the cerebral cortex after hypoxic-ischemic brain injury. J Craniofac Surg. 2013;24:2147–52.PubMed
39.
Le LT, Swingler TE, Crowe N, Vincent TL, Barter MJ, Donell ST, Delany AM, Dalmay T, Young DA, Clark IM. The microRNA-29 family in cartilage homeostasis and osteoarthritis. J Mol Med (Berl). 2016;94:583–96.
40.
Chen L, Li Q, Wang J, Jin S, Zheng H, Lin J, He F, Zhang H, Ma S, Mei J, Yu J. MiR-29b-3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN. J Cell Mol Med. 2017;21:3347–59.PubMedPubMedCentral
41.
Su T, Xiao Y, Xiao Y, Guo Q, Li C, Huang Y, Deng Q, Wen J, Zhou F, Luo XH. Bone marrow Mesenchymal stem cells-derived exosomal MiR-29b-3p regulates aging-associated insulin resistance. ACS Nano. 2019;13:2450–62.PubMed
42.
Zhou S, Lei D, Bu F, Han H, Zhao S, Wang Y. MicroRNA-29b-3p targets SPARC gene to protect cardiocytes against autophagy and apoptosis in hypoxic-induced H9c2 cells. J Cardiovasc Transl Res. 2019;12:358–65.PubMed
43.
Chang N, El-Hayek YH, Gomez E, Wan Q. Phosphatase PTEN in neuronal injury and brain disorders. Trends Neurosci. 2007;30:581–6.PubMed
44.
Liu C, Wu J, Xu K, Cai F, Gu J, Ma L, Chen J. Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. J Neurochem. 2010;112:1500–12.PubMed
45.
Arai K, Jin G, Navaratna D, Lo EH. Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke. FEBS J. 2009;276:4644–52.PubMedPubMedCentral
46.
Dzietko M, Derugin N, Wendland MF, Vexler ZS, Ferriero DM. Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl Stroke Res. 2013;4:189–200.PubMedPubMedCentral
47.
Madri JA. Modeling the neurovascular niche: implications for recovery from CNS injury. J Physiol Pharmacol. 2009;60(Suppl 4):95–104.PubMed
48.
Chen L, Zhu YM, Li YN, Li PY, Wang D, Liu Y, Qu YY, Zhu DL, Zhu YL. The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains. Neurol Res. 2017;39:795–802.PubMed
49.
Salomon C, Ryan J, Sobrevia L, Kobayashi M, Ashman K, Mitchell M, Rice GE. Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis. PLoS One. 2013;8:e68451.PubMedPubMedCentral
50.
Sahebi R, Langari H, Fathinezhad Z, Bahari Sani Z, Avan A, Ghayour Mobarhan M, Rezayi M. Exosomes: new insights into cancer mechanisms. J Cell Biochem. 2020;121:7–16.PubMed
51.
52.
Garcia NA, Ontoria-Oviedo I, Gonzalez-King H, Diez-Juan A, Sepulveda P. Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial cells. PLoS One. 2015;10:e0138849.PubMedPubMedCentral
53.
Huang JH, Xu Y, Yin XM, Lin FY. Exosomes Derived from miR-126-modified MSCs Promote Angiogenesis and Neurogenesis and Attenuate Apoptosis after Spinal Cord Injury in Rats. Neuroscience. 2020;424:133–45.
54.
Zhu ML, Yin YL, Ping S, Yu HY, Wan GR, Jian X, Li P. Berberine promotes ischemia-induced angiogenesis in mice heart via upregulation of microRNA-29b. Clin Exp Hypertens. 2017;39:672–9.PubMed
55.
Yu X, Peng Y, Liang H, Fu K, Zhao Z, Xie C, Zhou L, Zhang K. TSLP/TSLPR promote angiogenesis following ischemic stroke via activation of the PI3K/AKT pathway. Mol Med Rep. 2018;17:3411–7.PubMed
Metadata
Title
RETRACTED ARTICLE:Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway
Authors
Kun Hou
Guichen Li
Jinchuan Zhao
Baofeng Xu
Yang Zhang
Jinlu Yu
Kan Xu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-020-1725-8

Other articles of this Issue 1/2020

Journal of Neuroinflammation 1/2020 Go to the issue

Research

Cyclooxygenase-1 mediates neuroinflammation and neurotoxicity in a mouse model of retinitis pigmentosa

Research

Chemokine CXCL13 acts via CXCR5-ERK signaling in hippocampus to induce perioperative neurocognitive disorders in surgically treated mice

Review

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Research

Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system

Research

Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines

Research

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain