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Hypoxia/Reoxygenation-Preconditioned Human Bone Marrow-Derived Mesenchymal Stromal Cells Rescue Ischemic Rat Cortical Neurons by Enhancing Trophic Factor Release

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Abstract

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent a promising tool for stem cell-based therapies. However, the majority of MSCs fail to reach the injury site and have only minimal therapeutic effect. In this study, we assessed whether hypoxia/reoxygenation (H/R) preconditioning of human BM-MSCs could increase their functional capacity and beneficial effect on ischemic rat cortical neurons. Human BM-MSCs were cultured under hypoxia (1 % O2) and with long-term reoxygenation for various times to identify the optimal conditions for increasing their viability and proliferation. The effects of H/R preconditioning on the BM-MSCs were assessed by analyzing the expression of prosurvival genes, trophic factors, and cell migration assays. The functionally improved BM-MSCs were cocultured with ischemic rat cortical neurons to compare with normoxic cultured BM-MSCs. Although the cell viability and proliferation of BM-MSCs were reduced after 1 day of hypoxic culture (1 % O2), when this was followed by 5-day reoxygenation, the BM-MSCs recovered and multiplied extensively. The immunophenotype and trilineage differentiation of BM-MSCs were also maintained under this H/R preconditioning. In addition, the preconditioning enhanced the expression of prosurvival genes, the messenger RNA (mRNA) levels of various trophic factors and migration capacity. Finally, coculture with the H/R-preconditioned BM-MSCs promoted the survival of ischemic rat cortical neurons. H/R preconditioning of BM-MSCs increases prosurvival signals, trophic factor release, and cell migration and appears to increase their ability to rescue ischemic cortical neurons. This optimized H/R preconditioning procedure could provide the basis for a new strategy for stem cell therapy in ischemic stroke patients.

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Acknowledgments

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A101712).

The funding organization had no role in the design, execution, analysis, or preparation of this research.

Conflict of Interest

The authors have no potential conflicts of interest to report concerning this article.

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Authors and Affiliations

  1. Department of Neurology, Hanyang University College of Medicine, 17 Haengdang-dong, Seongdong-gu, Seoul, 133-792, Republic of Korea

    Young Seo Kim, Min Young Noh, Kyung Ah Cho, Hyemi Kim, Juhan Kim, Seong-Ho Koh & Seung Hyun Kim

  2. Department of Pharmacology, School of Medicine, CHA University, Seongnam, South Korea

    Min-Soo Kwon

  3. Bioengineering Institute, Corestem, Inc., Seoul, South Korea

    Kyung Suk Kim

  4. Department of Translational Medicine, Hanyang University, Graduate School of Biomedical Science & Engineering, Seoul, South Korea

    Seong-Ho Koh & Seung Hyun Kim

  5. Department of Neurology, Hanyang University Guri Hospital, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, 471-701, Republic of Korea

    Seong-Ho Koh

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  1. Young Seo Kim
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  2. Min Young Noh
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  4. Hyemi Kim
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  6. Kyung Suk Kim
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  7. Juhan Kim
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  8. Seong-Ho Koh
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  9. Seung Hyun Kim
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Corresponding authors

Correspondence to Seong-Ho Koh or Seung Hyun Kim.

Additional information

Young Seo Kim, Min Young Noh, and Kyung Ah Cho contributed equally to this work.

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Kim, Y.S., Noh, M.Y., Cho, K.A. et al. Hypoxia/Reoxygenation-Preconditioned Human Bone Marrow-Derived Mesenchymal Stromal Cells Rescue Ischemic Rat Cortical Neurons by Enhancing Trophic Factor Release. Mol Neurobiol 52, 792–803 (2015). https://doi.org/10.1007/s12035-014-8912-5

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  • DOI: https://doi.org/10.1007/s12035-014-8912-5

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