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Adipose tissue-derived mesenchymal stem cells cultured at high cell density express brain-derived neurotrophic factor and exert neuroprotective effects in a 6-hydroxydopamine rat model of Parkinson’s disease

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Abstract

Mesenchymal stem cells (MSCs) secrete neurotrophic factors, and have been reported to improve functional outcomes in animal models of neurodegenerative diseases such as cerebral ischemia, stroke, spinal cord lesions, and Parkinson’s disease. Previously, we found that adipose tissue-derived mesenchymal stem cells (ASCs) cultured at high cell density (HD-ASCs) expressed interferon-beta (IFN-β). Here we demonstrate that ASCs expressing IFN-β also express brain-derived neurotrophic factor (BDNF). Growth rates of neuroblastoma cells (SK-N-BE(2)C) were increased when co-cultured with HD-ASCs or treated with concentrated medium obtained from HD-ASCs (HD-ASC-CM). The HD-ASC-CM induced AKT phosphorylation in SK-N-BE(2)C cells, and AKT inhibition by Ly294002 reduced cell viability of SK-N-BE(2)C cells. Additionally, a protective effect on SK-N-BE(2)C cells exposed to 6-hydroxydopamine (6-OHDA) was observed in the HD-ASC-CM or brain-derived neurotrophic factor (BDNF) treated cells. The protective effect of the HD-ASC-CM was neutralized by anti-BDNF antibody. In the 6-OHDA-induced Parkinson’s disease rat model, ASCs reduced amphetamine-induced rotations and a greater number of tyrosine hydroxylase (TH)-positive cells were observed in the HD-ASCs-injected group compared with sham controls and the low density cultured ASC-injected group. Moreover, the expression of BDNF, nerve growth factor (NGF), TH, and proliferating cell nuclear antigen (PCNA) in ipsilateral midbrain tissues including substantia nigra pars compacta (SNc) was increased by transplantation of HD-ASCs. These data indicate that HD-ASCs may induce neuroprotective effects through BDNF expression and subsequent increase of proliferation in neuronal cells both in vitro and in vivo.

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2012R1A1A2004981).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Wonju College of Medicine, Yonsei University, Wonju, 220-701, Republic of Korea

    Joon Beom Park, Seong Joon Kang & Keum Seok Bae

  2. Department of Anatomy, Wonju College of Medicine, Yonsei University, Wonju, 220-701, Republic of Korea

    ** Suk Lee & Byung Pil Cho

  3. Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju, 220-701, Republic of Korea

    Ki-Jong Rhee

  4. Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei University, Wonju, 220-701, Republic of Korea

    Soon Koo Baik, Ji-Eun Oh & Young Woo Eom

  5. Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Kangwon-do, 220-701, Republic of Korea

    Soon Koo Baik

  6. Department of Plastic and Reconstructive Surgery, Wonju College of Medicine, Yonsei University, Wonju, 220-701, Republic of Korea

    Jiye Kim

  7. Department of Otorhinolaryngology, Wonju College of Medicine, Yonsei University, Wonju, 220-701, Republic of Korea

    Dong-Joon Park

  8. Pharmicell Co., Ltd, Sungnam, 462-737, Republic of Korea

    Ha Cheol Shin, Yong Man Kim & Hyun Soo Kim

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  1. Joon Beom Park
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  2. ** Suk Lee
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  10. Ha Cheol Shin
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Correspondence to Young Woo Eom.

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Joon Beom Park and ** Suk Lee have contributed equally to this work.

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Park, J.B., Lee, J.S., Cho, B.P. et al. Adipose tissue-derived mesenchymal stem cells cultured at high cell density express brain-derived neurotrophic factor and exert neuroprotective effects in a 6-hydroxydopamine rat model of Parkinson’s disease. Genes Genom 37, 213–221 (2015). https://doi.org/10.1007/s13258-014-0239-0

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