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Therapeutic Potential of a Combination of Electroacupuncture and TrkB-Expressing Mesenchymal Stem Cells for Ischemic Stroke

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Abstract

We prepared and grafted tropomyosin receptor kinase B (TrkB) gene-transfected mesenchymal stem cells (TrkB-MSCs) into the ischemic penumbra and investigated whether electroacupuncture (EA) treatment could promote functional recovery from ischemic stroke. For the behavioral test, TrkB-MSCs+EA resulted in significantly improved motor function compared to that obtained with MSCs+EA or TrkB-MSCs alone. At 30 days after middle cerebral artery occlusion (MCAO), the largest number of grafted MSCs was detected in the TrkB-MSC+EA group. Some differentiation into immature neuroblasts and astrocytes was detected; however, only a few mature neuron-like cells were found. Compared to other treatments, TrkB-MSCs+EA upregulated the expression of mature brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT4) and induced the activation of TrkB receptor and its transcription factor cAMP response element-binding protein (CREB). At 60 days after MCAO, EA highly promoted the differentiation of TrkB-MSCs into mature neuron-like cells compared to the effect in MSCs. A selective TrkB antagonist, ANA-12, reverted the effect of TrkB-MSCs+EA in motor function recovery and survival of grafted MSCs. Our results suggest that EA combined with grafted TrkB-MSCs promotes the expression of BDNF and NT4, induces the differentiation of TrkB-MSCs, and improves motor function. TrkB-MSCs could serve as effective therapeutic agents for ischemic stroke if used in combination with BDNF/NT4-inducing therapeutic approaches.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

BMP:

Bone morphogenetic protein

CREB:

cAMP response element-binding protein

DAPI:

4′,6-Diamidino-2-phenylindole

Dcx:

Doublecortin

EA:

Electroacupuncture

FGF:

Fibroblast growth factor

GFAP:

Glial fibrillary acidic protein

MSCs:

Mesenchymal stem cells

NeuN:

Neuronal nuclei

NTFs:

Neurotrophic factors

NT4:

Neurotrophin-4/5

TrkB:

Tropomyosin receptor kinase B

VEGF:

Vascular endothelial growth factor

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (2014R1A5A2009936). This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (2015R1A2A2A03006712).

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Authors and Affiliations

  1. Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 50612, Republic of Korea

    Sung Min Ahn, Yu Ri Kim, Ki Tae Ha, Seo-Yeon Lee, Hwa Kyoung Shin & Byung Tae Choi

  2. Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 50612, Republic of Korea

    Yu Ri Kim, Ki Tae Ha, Hwa Kyoung Shin & Byung Tae Choi

  3. Department of Rehabilitation Medicine, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea

    Yong-Il Shin

  4. Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, 50612, Republic of Korea

    Ki Tae Ha, Seo-Yeon Lee, Hwa Kyoung Shin & Byung Tae Choi

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  1. Sung Min Ahn
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  2. Yu Ri Kim
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  3. Yong-Il Shin
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Contributions

All authors contributed extensively to this work. S.M.A. and B.T.C. conceived and designed the experiments; S.M.A., Y.R.K., and S.Y.L. performed the experiments; S.M.A., Y.I.S., K.T.H., H.K.S., and B.T.C. analyzed the data; and S.M.A. and B.T.C. wrote the manuscript.

Corresponding author

Correspondence to Byung Tae Choi.

Ethics declarations

The study was approved by the Pusan National University Animal Care and Use Committee in accordance with the National Institutes of Health Guidelines (Approval No. PNU-2017-1448).

Conflict of Interest

The authors declare that there are no competing interests.

Electronic supplementary material

Supplemental information includes the results of the passive avoidance test and immunofluorescence staining.

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Ahn, S.M., Kim, Y.R., Shin, YI. et al. Therapeutic Potential of a Combination of Electroacupuncture and TrkB-Expressing Mesenchymal Stem Cells for Ischemic Stroke. Mol Neurobiol 56, 157–173 (2019). https://doi.org/10.1007/s12035-018-1067-z

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