Skip to main content

The neuroprotective effect of mesenchymal stem cells is mediated through inhibition of apoptosis in hypoxic ischemic injury

World Journal of Pediatrics volume 16, pages 193–200 (2020)Cite this article

Abstract

Background

Neonatal hypoxia ischemia causes severe brain damage. Stem cell therapy is a promising method for treating neuronal diseases. Clinical translation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for the recovery of neurons after hypoxic ischemic encephalopathy (HIE) may represent an effective therapy.

Methods

Primary neurons were exposed to oxygen–glucose deprivation (OGD) and subsequently cocultured with UC-MSCs. Apoptosis was examined by Annexin V-FITC-PI. Genes related to apoptosis were detected using RT-PCR and western-blot analyses. Using an in vivo model, HIE was induced in postnatal day 7 mice, and UC-MSCs were transplanted via the intraventricular route. UC-MSC migration was investigated by immunofluorescence, and lesion volumes were measured by TTC staining. Apoptosis in injured brain cells was detected by the TUNEL assay. RT-PCR and ELISA were used to detect the expression of inflammatory factors in cells and animal tissues.

Results

Flow cytometry analysis revealed that apoptosis in injured neurons was inhibited by UC-MSCs. The RT-PCR and western blot results indicated that coculture inhibited the expression of proapoptotic genes and upregulated expression of antiapoptotic genes. In the animal model, transplanted UC-MSCs migrated toward the cerebral lesion site and decreased the lesion extent in HIE. TUNEL staining showed that the MSC group exhibited significantly reduced numbers of TUNEL-positive cells. RT-PCR and ELISA showed that UC-MSCs inhibited the upregulation of TNF-α and IL-1β in response to hypoxic ischemic injury.

Conclusion

These results indicate that UC-MSCs exert neuroprotective effects against hypoxic ischemic injury by inhibiting apoptosis, and the mechanism appears to be through alleviating the inflammatory response.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Yao Y, Zheng XR, Zhang SS, Wang X, Yu XH, Tan JL, et al. Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage. Neural Regen Res. 2016;11:1456–63.

    PubMed  PubMed Central  Google Scholar 

  2. Zhou X, Gu J, Gu Y, He M, Bi Y, Chen J, et al. Human umbilical cord-derived mesenchymal stem cells improve learning and memory function in hypoxic-ischemic brain-damaged rats via an IL-8-mediated secretion mechanism rather than differentiation pattern induction. Cell Physiol Biochem. 2015;35:2383–401.

    CAS  Article  Google Scholar 

  3. Zhang J, Yang C, Chen J, Luo M, Qu Y, Mu D, et al. Umbilical cord mesenchymal stem cells and umbilical cord blood mononuclear cells improve neonatal rat memory after hypoxia-ischemia. Behav Brain Res. 2019;19:56–63.

    Article  Google Scholar 

  4. Andrzejewska A, Lukomska B, Janowski M. Mesenchymal stem cells: from roots to boost. Stem Cells. 2019;37:855–64.

    Article  Google Scholar 

  5. Sugiyama Y, Sato Y, Kitase Y, Suzuki T, Kondo T, Mikrogeorgiou A, 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. Front Neurol. 2018;9:757.

    Article  Google Scholar 

  6. Wagenaar N, Nijboer CH, van Bel F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol. 2017;59:997–1003.

    Article  Google Scholar 

  7. Zhang HL, Xie XF, Xiong YQ, Liu SM, Hu GZ, Cao WF, et al. Comparisons of the therapeutic effects of three different routes of bone marrow mesenchymal stem cell transplantation in cerebral ischemic rats. Brain Res. 2018;1680:143–54.

    CAS  Article  Google Scholar 

  8. Mukai T, Tojo A, Nagamura-Inoue T. Mesenchymal stromal cells as a potential therapeutic for neurological disorders. Regen Ther. 2018;9:32–7.

    Article  Google Scholar 

  9. Zhao C, Zhang L, Kong W, Liang J, Xu X, Wu H, et al. Umbilical cord-derived mesenchymal stem cells inhibit cadherin-11 expression by fibroblast-like synoviocytes in rheumatoid arthritis. J Immunol Res. 2015;2015:137695.

    PubMed  PubMed Central  Google Scholar 

  10. Chandravanshi B, Bhonde RR. Human umbilical cord-derived stem cells: isolation, characterization, differentiation, and application in treating diabetes. Crit Rev Biomed Eng. 2018;46:399–412.

    Article  Google Scholar 

  11. Archambault J, Moreira A, McDaniel D, Winter L, Sun L, Hornsby P. Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: a systematic review and meta-analysis of preclinical studies. PLoS ONE. 2017;12:e0189895.

    Article  Google Scholar 

  12. Xie B, Gu P, Wang W, Dong C, Zhang L, Zhang J, et al. Therapeutic effects of human umbilical cord mesenchymal stem cells transplantation on hypoxic ischemic encephalopathy. Am J Transl Res. 2016;8:3241–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu LH, Bai X, Zhang N, Wang SY, Li W, Jiang L. Improvement of human umbilical cord mesenchymal stem cell transplantation on glial cell and behavioral function in a neonatal model of periventricular white matter damage. Brain Res. 2014;1563:13–211.

    CAS  Article  Google Scholar 

  14. Ding HF, Zhang H, Ding HF, Li D, Yi XH, Gao XY, et al. Therapeutic effect of placenta-derived mesenchymal stem cells on hypoxic-ischemic brain damage in rats. World J Pediatr. 2015;11:74–82.

    CAS  Article  Google Scholar 

  15. Zheng Z, Zhang L, Qu Y, Xiao G, Li S, Bao S, et al. Mesenchymal stem cells protect against hypoxia-ischemia brain damage by enhancing autophagy through brain derived neurotrophic factor/mammalin target of rapamycin signaling pathway. Stem Cells. 2018;36:1109–21.

    CAS  Article  Google Scholar 

  16. He M, Shi X, Yang M, Yang T, Li T, Chen J. Mesenchymal stem cells-derived IL-6 activates AMPK/mTOR signaling to inhibit the proliferation of reactive astrocytes induced by hypoxic-ischemic brain damage. Exp Neurol. 2019;311:15–32.

    CAS  Article  Google Scholar 

  17. Gu Y, He M, Zhou X, Liu J, Hou N, Bin T, et al. Endogenous IL-6 of mesenchymal stem cell improves behavioral outcome of hypoxic-ischemic brain damage neonatal rats by supressing apoptosis in astrocyte. Sci Rep. 2016;6:18587.

    CAS  Article  Google Scholar 

  18. Thornton C, Hagberg H. Role of mitochondria in apoptotic and necroptotic cell death in the developing brain. Clin Chim Acta. 2015;451(Pt A):35–8.

    CAS  Article  Google Scholar 

  19. Shen J, Xu S, Zhou H, Liu H, Jiang W, Hao J, et al. IL-1L induces apoptosis and autophagy via mitochondria pathway in human degenerative nucleus pulposus cells. Sci Rep. 2017;7:41067.

    CAS  Article  Google Scholar 

Download references

Funding

This work was supported by Grants from the National Nature Science Foundation of China (No. 81200950), the Science and Technology Development Project of Shandong Province (No. 2014GSF118173), the Chinese Postdoctoral Science Foundation (No. 2016M590637), and Nature Science Foundation of Shandong province (ZR2019PH055).

Author information

Affiliations

  1. Laboratory of Cell Therapy and Translational Medicine, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, 250013, China

    Fang Li, Kun Zhang, Hua Liu, Dong-Jie Xiao & Yun-Shan Wang

  2. Shandong Research Center of Transplantation and Tissue, Jinan, 250013, China

    Fang Li, Kun Zhang, Hua Liu, Dong-Jie Xiao & Yun-Shan Wang

  3. Clinical Laboratory, The People’s Hospital of Bozhou, Bozhou, 236800, China

    Tan Yang

Authors
  1. Fang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dong-Jie Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun-Shan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FL cultured the cell lines and performed the experiments in vitro. KZ detected the gene and protein expression in animal tissue. HL devised the protocol and wrote the manuscript. Tan Yang contributed to the animal model. DX conceived the original idea and supervised the experiments. YW approved the final version. The manuscript represents our original unpublished research results and did not submitting to other journals.

Corresponding author

Correspondence to Hua Liu.

Ethics declarations

Ethical approval

Informed content was obtained from family members of the newborns and the experimental protocol was approved by the Ethics Committee of Jinan central Hospital.

Conflict of interest

No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, F., Zhang, K., Liu, H. et al. The neuroprotective effect of mesenchymal stem cells is mediated through inhibition of apoptosis in hypoxic ischemic injury. World J Pediatr 16, 193–200 (2020). https://doi.org/10.1007/s12519-019-00310-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-019-00310-x

Keywords

  • Apoptosis
  • Hypoxic ischemic encephalopathy
  • Mesenchymal stem cell
  • Transplantation