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Therapeutic efficacy of intravenous infusion of mesenchymal stem cells in rat perinatal brain injury

Pediatric Research volume 94, pages 1921–1928 (2023)Cite this article

Abstract

Background

Perinatal brain injury is multifactorial and primarily associated with brain prematurity, inflammation, and hypoxia–ischemia. Although recent advances in perinatal medicine　have improved the survival rates of preterm infants, neurodevelopmental disorders remain a significant complication. We tested whether the intravenous infusion of mesenchymal stem cells (MSCs) had therapeutic efficacy against perinatal brain injury in rats.

Methods

Pregnant rats at embryonic day (E) 18 received lipopolysaccharide and the pups were born at E21. On postnatal day (PND) 7, the left common carotid artery of each pup was ligated, and they were exposed to 8% oxygen for 2 h. They were randomized on PND10, and MSCs or vehicle were intravenously infused. We performed behavioral assessments, measured brain volume using MRI, and performed histological analyses on PND49.

Results

Infused MSCs showed functional improvements in our model. In vivo MRI revealed that MSC infusion increased non-ischemic brain volume compared to the vehicle group. Histological analyses showed that cortical thickness, the number of NeuN+ and GAD67+ cells, and synaptophysin density in the non-ischemic hemisphere in the MSC group were greater than the vehicle group, but less than the control group.

Conclusions

Infused MSCs improve sensorimotor and cognitive functions in perinatal brain injury and enhance neuronal growth.

Impact

  • Intravenous infusion of MSCs improved neurological function in rats with perinatal brain injury, including motor, sensorimotor, cognitive, spatial, and learning memory.

  • Infused MSCs increased residual (non-ischemic) tissue volume, number of neuronal cells, GABAergic cells, and cortical synapses in the contralesional (right) hemisphere.

  • Intravenous administration of MSC might be suitable for the treatment of perinatal brain injury.

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Fig. 1: Experimental protocol.
Fig. 2: Functional Improvement after intravenous infusion of MSCs.
Fig. 3: Infused MSC facilitated the growth of the residual brain with in vivo MRI (T2-weighted images) analysis.
Fig. 4: Histological analyses after systemic administration of MSCs.
Fig. 5: Distribution of GFP-MSCs in the MSC-treated rats.
Fig. 6: Evaluation of neural tracts that run through bilateral internal capsule using ex vivo diffusion-tensor imaging (DTI) tractography.

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Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We are thankful to the National BioResource Project - Rat (http://www.anim.med.kyoto-u.ac.jp/NBR/) for providing this rat strain (W-Tg (CAG-GFP) 184Ys).

Funding

This work was supported in part by the JSPS KAKENHI grant (grant number 20K08163) and the RR&D Service of the US Department of Veterans Affairs (grants B7335R and B9260L).

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Authors and Affiliations

  1. Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Kojiro Terada, Yusuke Iizuka, Shinobu Fukumura & Takeshi Tsugawa

  2. Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Kojiro Terada, Masanori Sasaki, Hiroshi Nagahama, Yuko Kataoka-Sasaki, Shinichi Oka, Ryo Ukai, Takahiro Yokoyama, Yusuke Iizuka & Osamu Honmou

  3. Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

    Masanori Sasaki, Jeffery D. Kocsis & Osamu Honmou

  4. Division of Radioisotope Research, Biomedical Research, Education and Instrumentation Center, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8556, Japan

    Hiroshi Nagahama

  5. Department of Perinatal Medicine, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Takuro Sakai

  6. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Jeffery D. Kocsis

  7. Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA

    Jeffery D. Kocsis

Authors
  1. Kojiro Terada
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  2. Masanori Sasaki
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  9. Takuro Sakai
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  10. Shinobu Fukumura
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  11. Takeshi Tsugawa
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  12. Jeffery D. Kocsis
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  13. Osamu Honmou
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Contributions

Each author has met the Pediatric Research authorship requirements. Each author completed the following criteria: (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.

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Correspondence to Masanori Sasaki.

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Terada, K., Sasaki, M., Nagahama, H. et al. Therapeutic efficacy of intravenous infusion of mesenchymal stem cells in rat perinatal brain injury. Pediatr Res 94, 1921–1928 (2023). https://doi.org/10.1038/s41390-023-02717-9

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