Chinese Medical E-ournals Database

Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition) ›› 2020, Vol. 16 ›› Issue (04): 386 -391. doi: 10.3877/cma.j.issn.1673-5250.2020.04.003

Special Issue:

Forum

Neuroprotective effect of mesenchymal stem cells on neonatal hypoxic-ischemic brain damage

Jing Yuan1, Chao Yang2, Juan Chen1,()   

  1. 1. Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
    2. Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank, Chengdu 610036, Sichuan Province, China
  • Received:2020-03-30 Revised:2020-07-02 Published:2020-08-01
  • Corresponding author: Juan Chen
  • About author:
    Corresponding author: Chen Juan, Email:
  • Supported by:
    Key Project of Health and Family Planning Commission of Sichuan Province(16ZD019)

Neonatal hypoxic-ischemic encephalopathy (HIE) is a kind of hypoxic-ischemic brain damage (HIBD) caused by perinatal asphyxia, and it is the main cause of acute neonatal death and long-term neurological diseases. The current strategies for treatment of HIE are symptomatic support therapy, while there is no curative treatment for HIE so far. However, the clinical efficacy of this approach is limited and cannot promote repair or regeneration of damaged nerves. Mesenchymal stem cell transplantation (MSCT), as a new strategy for the treatment of neonatal HIE, has exhibited neuroprotective effects in HIBD model animal. Its mechanism is complex, such as secreting extracellular vesicles, regulating immunity, promoting the repair and regeneration of neurons, anti-apoptosis and anti-oxidation. This article summarizes the latest research progresses on possible mechanisms of mesenchymal stem cell (MSC) in neuroprotective effect on HIBD animal disease model.

[1]
Li B, Concepcion K, Meng X, et al. Brain-immune interactions in perinatal hypoxic-ischemic brain injury [J]. Prog Neurobiol, 2017,159(1): 50-68. DOI:10.1016/j.pneurobio.2017.10.006.
[2]
Yildiz EP, Ekici B, Tatli B. Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment [J]. Exp Rev Neurother, 2017, 17(5): 449-459. DOI: 10.1080/14737175.2017.1259567.
[3]
Wassink G, Gunn ER, Drury PP, et al. The mechanisms and treatment of asphyxial encephalopathy [J]. Front Neurosci, 2014, 8(1): 40. DOI: 10.3389/fnins.2014.00040.
[4]
Reinboth BS, Köster C, Abberger H, et al. Endogenous hypothermic response to hypoxia reduces brain injury: implications for modeling hypoxic-ischemic encephalopathy and therapeutic hypothermia in neonatal mice [J]. Exp Neurol, 2016, 283(Pt A): 264-275. DOI: 10.1016/j.expneurol.2016.06.024.
[5]
Chen X, Peng W, Zhang Z, et al. Efficacy and safety of selective brain hypothermia therapy on neonatal hypoxic-ischemic encephalopathy [J]. Chin Crit Care Med, 2018, 30(11): 1046-1050. DOI: 10.3760/cma.j.issn.2095-4352.2018.011.007.
[6]
El Omar R, Beroud J, Stoltz JF, et al. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? [J]. Tissue Eng Part B Rev, 2014, 20(5): 523-544. DOI: 10.1089/ten.TEB.2013.0664.
[7]
束庆,范晴晴,刘蕴星,等. 间充质干细胞移植在治疗自身免疫性疾病中的应用进展[J]. 药学进展,2019, 43(4): 276-281.
[8]
Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt′s macular dystrophy: follow-up of two open-label phase 1/2 studies [J]. Lancet, 2015, 385(9967): 509-516. DOI: 10.1016/S0140-6736(14)61376-3.
[9]
Hawkins KE, Corcelli M, Dowding K, et al. Embryonic stem cell-derived mesenchymal stem cells (MSC) have a superior neuroprotective capacity over fetal MSC in the hypoxic-ischemic mouse brain [J]. Stem Cells Transl Med, 2018, 7(5): 439-449. DOI: 10.1002/sctm.17-0260.
[10]
Herz J, Koster C, Reinboth BS, et al. Interaction between hypothermia and delayed mesenchymal stem cell therapy in neonatal hypoxic-ischemic brain injury [J]. Brain Behav Immun, 2018, 70(1): 118-130. DOI: 10.1016/j.bbi.2018.02.006.
[11]
Ophelders DR, Wolfs TG, Jellema RK, et al. Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia [J]. Stem Cells Transl Med, 2016, 5(6): 754-763. DOI: 10.5966/sctm.2015-0197.
[12]
Zhang J, Yang C, Chen J, et al. Umbilical cord mesenchymal stem cells and umbilical cord blood mononuclear cells improve neonatal rat memory after hypoxia-ischemia [J]. Behav Brain Res, 2019, 362(1): 56-63. DOI: 10.1016/j.bbr.2019.01.012.
[13]
Kong D, Zhu J, Liu Q, et al. Mesenchymal stem cells protect neurons against hypoxic-ischemic injury via inhibiting parthanatos, necroptosis, and apoptosis, but not autophagy [J]. Cell Mol Neurobiol, 2017, 37(2): 303-313. DOI: 10.1007/s10571-016-0370-3.
[14]
Li PK, Kandoi S, Misra R, et al. The mesenchymal stem cell secretome: a new paradigm towards cell-free therapeutic mode in regenerative medicine [J]. Cytokine Growth Factor Rev, 2019, 46(1): 1-9. DOI: 10.1016/j.cytogfr.2019.04.002.
[15]
Study of hCT-MSC in newborn infants with moderate or severe HIE [EB/OL]. (2018-08-17)[2020-01-11].

URL    
[16]
黄庆雷,沈丽,邓钺. 间充质干细胞作用机制的研究进展[J]. 中国科学(生命科学), 2019, 49(2): 108-128. DOI: 10.1360/N052018-00175.
[17]
Rani S, Ryan AE, Griffin MD, et al. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications [J]. Mol Ther, 2015, 23(5): 812-823. DOI: 10.1038/mt.2015.44.
[18]
Ek CJ, D′Angelo B, Baburamani AA, et al. Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia [J]. J Cereb Blood Flow Metab, 2015, 35(5): 818-827. DOI: 10.1038/jcbfm.2014.255.
[19]
Gussenhoven R, Klein L, Ophelders D, et al. Annexin A1 as neuroprotective determinant for blood-brain barrier integrity in neonatal hypoxic-ischemic encephalopathy [J]. J Clin Med, 2019, 8(2): 137. DOI: 10.3390/jcm8020137.
[20]
Sisa C, Kholia S, Naylor J, et al. Mesenchymal stromal cell derived extracellular vesicles reduce hypoxia-ischaemia induced perinatal brain injury [J]. Front Physiol, 2019, 10(1): 282. DOI: 10.3389/fphys.2019.00282.
[21]
Ziemka-Nalecz M, Jaworska J, Zalewska T. Insights into the neuroinflammatory responses after neonatal hypoxia-ischemia [J]. J Neuropathol Exp Neurol, 2017, 76(8): 644-654. DOI: 10.1093/jnen/nlx046.
[22]
Zhu LH, Bai X, Zhang N, et al. Improvement of human umbilical cord mesenchymal stem cell transplantation on glial cell and behavioral function in a neonatal model of periventricular white matter damage [J]. Brain Res, 2014, 1563(1): 13-21. DOI: 10.1016/j.brainres.2014.03.030.
[23]
Murry PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines [J]. Immunity, 2014, 41(1): 14-20. DOI: 10.1016/j.immuni.2014.06.008.
[24]
Almad A, Maragakis NJ. A stocked toolbox for understanding the role of astrocytes in disease [J]. Nat Rev Neurol, 2018,14(6): 351-362. DOI: 10.1038/s41582-018-0010-2.
[25]
Pekny M, Pekna M. Reactive gliosis in the pathogenesis of CNS diseases [J]. Biochim Biophys Acta, 2016, 1862(3): 483-491. DOI:10.1016/j.bbadis.2015.11.014.
[26]
Wang Y, Chen X, Cao W, et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications [J]. Nat Immunol, 2014, 15(11): 1009-1016. DOI: 10.1038/ni.3002.
[27]
Li Z, Ye H, Cai X, et al. Bone marrow-mesenchymal stem cells modulate microglial activation in the peri-infarct area in rats during the acute phase of stroke [J]. Brain Res Bull, 2019, 153(1): 324-333. DOI: 10.1016/j.brainresbull.2019.10.001.
[28]
Mayer AM, Murphy J, MacAdam D, et al. Classical and alternative activation of cyanobacterium oscillatoria sp. lipopolysaccharide-treated rat microglia in vitro[J]. Toxicol Sci, 2016,149(2): 484-495. DOI: 10.1093/toxsci/kfv251.
[29]
Tang Z, Gan Y, Liu Q, et al. CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke [J]. J Neuroinflammation, 2014, 11(1): 26. DOI: 10.1186/1742-2094-11-26.
[30]
Sugiyama Y, Sato Y, Kitase Y, et al. Intravenous administration of bone marrow-derived mesenchymal stem cell, but not adipose tissue-derived stem cell, ameliorated the neonatal hypoxic-ischemic brain injury by changing cerebral inflammatory state in rat [J]. Front Neurol, 2018, 9(1): 757. DOI: 10.3389/fneur.2018.00757.
[31]
He M, Shi X, Yang M, et al. Mesenchymal stem cells-derived IL-6 activates AMPK/mTOR signaling to inhibit the proliferation of reactive astrocytes induced by hypoxic-ischemic brain damage [J]. Exp Neurol, 2019, 311(1): 15-32. DOI: 10.1016/j.expneurol.2018.09.006.
[32]
Ding H, Zhang H, Ding H, et al. Transplantation of placenta-derived mesenchymal stem cells reduces hypoxic-ischemic brain damage in rats by ameliorating the inflammatory response [J]. Cell Mol Immunol, 2017, 14(8): 693-701. DOI: 10.1038/cmi.2015.99.
[33]
Purger D, Gibson EM, Monje M. Myelin plasticity in the central nervous system [J]. Neuropharmacology, 2016, 110(Pt B): 563-573. DOI: 10.1016/j.neuropharm.2015.08.001.
[34]
van Velthoven CT, Kavelaars A, Heijnen CJ. Mesenchymal stem cells as a treatment for neonatal ischemic brain damage [J]. Pediatr Res, 2012, 71(4 Pt 2): 474-481. DOI: 10.1038/pr.2011.64.
[35]
Yang Z, You Y, Levison SW. Neonatal hypoxic/ischemic brain injury induces production of calretinin-expressing interneurons in the striatum [J]. J Comp Neurol, 2008, 511(1): 19-33. DOI: 10.1002/cne.21819.
[36]
Cameron SH, Alwakeel AJ, Goddard L, et al. Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia [J]. Mol Cell Neurosci, 2015, 68(1): 56-72. DOI: 10.1016/j.mcn.2015.03.019.
[37]
Xu J, Feng Z, Wang X, et al. hUC-MSC exert a neuroprotective effect via anti-apoptotic mechanisms in a neonatal HIE rat model [J]. Cell Transplant, 2019, 28(12): 1552-1559. DOI: 10.1177/0963689719874769.
[38]
Qin X, Cheng J, Zhong Y, et al. Mechanism and treatment related to oxidative stress in neonatal hypoxic-ischemic encephalopathy [J]. Front Mol Neurosci, 2019, 12(1): 88. DOI: 10.3389/fnmol.2019.00088.
[39]
Zhao M, Zhu P, Fujino M, et al. Oxidative stress in hypoxic-ischemic encephalopathy: molecular mechanisms and therapeutic strategies [J]. Int J Mol Sci, 2016, 17(12): 2078. DOI: 10.3390/ijms17122078.
[40]
Ding HF, Zhang H, Ding HF, et al. Therapeutic effect of placenta-derived mesenchymal stem cells on hypoxic-ischemic brain damage in rats [J]. World J Pediatr, 2015, 11(1): 74-82. DOI: 10.1007/s12519-014-0531-8.
[41]
Li X, Michaeloudes C, Zhang Y, et al. Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways [J]. J Allergy Clin Immunol, 2018, 141(5): 1634-1645. DOI: 10.1016/j.jaci.2017.08.017.
[42]
Galipeau J, Sensebe L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities[J]. Cell Stem Cell, 2018, 22(6): 824-833. DOI: 10.1016/j.stem.2018.05.004.
[43]
Yang C, Chen Y, Zhong LW, et al. Homogeneity and heterogeneity of biological characteristics in mesenchymal stem cells from human umbilical cords and exfoliated deciduous teeth [J]. Biochem Cell Biol, 2020, 98(3): 415-425. DOI: 10.1139/bcb-2019-0253.
[1] Yangwenxiang Wei, Haoran Huang, Yuhao Liu, Zhenqiu Chen, Haibin Wang, Chi Zhou. Outlooks and challenges in cell therapy of osteonecrosis of femoral head[J]. Chinese Journal of Joint Surgery(Electronic Edition), 2023, 17(05): 694-700.
[2] Yang Yang, Cheng Wang, Wentu Zhou, Bing Zhou. Caveolae/Caveolin-1 regulates osteogenic differentiation of mouse BMSCs together with membrane cholesterol[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(03): 137-142.
[3] Haiyan Sun, Shiyan Zhou, Shanshan Zhang, Yan Zhang, Qian Zhang. Advances in potential therapeutic mechanisms of mesenchymal stem cells and their exosomes in high altitude pulmonary edema[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(03): 186-190.
[4] Shuxun Ling, Yue Tu, Siyi Liu. Visualization analysis on knowledge map of mesenchymal stem cells in the research field of chronic kidney disease[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(02): 73-82.
[5] Juan Wang, Ye Liu, Wei Xiong, Cailei Jiang, Yan He, Qingsong Ye. A novel therapeutic mechanism for mesenchymal stem cells to alleviate oxidative stress in Alzheimer's disease[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(02): 93-106.
[6] Guohao Liang, Qian Zhang, Yan Zhang. Advance in mesenchymal stem cells for the treatment of cardiovascular diseases in the low- oxygen environment of plateau[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(02): 107-112.
[7] Wenyu Zhang, Yuxiang Huang. Research progress in large-scale cultivation of mesenchymal stem cells in vitro[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(06): 370-376.
[8] Jiaming Fan, Ziying Yang, Zhenhui Feng, Yihuan Chen, Yutong Wang, Zhenya Shen. Analysis of differential miRNA expression related to the efficacy of stem cell transplantation in dilated cardiomyopathy[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(05): 288-298.
[9] Jun Wu, Lixuan Chen, Yang Xiao. Analysis of dual filing research projects on stem cells in China[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(05): 304-309.
[10] Ye Li, Jie He, Jinxiu Hu, Jinxiang Wang, Chuan Tian, Hang Pan, Mengdie Chen, Xiaojuan Zhao, Li Ye, Min Zhang, Xinghua Pan. Highly active mesenchymal stem cells interfere with ovarian aging in macaques[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 210-219.
[11] Huiling Long, Mi Lin, Ting Shao. Research progress and application of three-dimensional spherical mesenchymal stem cell culture technology[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 229-234.
[12] Yafei Lu, Shaohua Huangfu, Chuanxue Ma, Bin Jiang. Research progress on the treatment of anal fistula surgery with mesenchymal stem cells[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2024, 13(03): 242-249.
[13] Jingxuan Shi, Yuanyuan Jiao, Jingwei Tian, Li Zhuo. Efficacy of mesenchymal stem cells-derived exosomes in the treatment of diabetic kidney disease in animals: a meta-analysis[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2024, 13(02): 79-86.
[14] Zhangning Fu, Xiaodong Geng, Yongjun Zhang, Yuping Lu, Guannan Sun, Yifan Zhang, Guangyan Cai, Xiangmei Chen, Quan Hong. Research progress on the mechanism of mesenchymal stem cells in promoting renal injury repair[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2024, 13(02): 87-91.
[15] Yifan Zhang, Xiaodong Geng, Yuwei Ji, Keying Zhang, Shupeng Lin, Guangyan Cai, Xiangmei Chen, Quan Hong. LRG1 enhanced the efficacy of mesenchymal stem cells in the treatment of acute kidney injury[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2024, 13(01): 16-25.
Viewed
Full text


Abstract