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Stem Cell Reviews and Reports

, Volume 10, Issue 6, pp 761–771 | Cite as

PSA-NCAM+ Neural Precursor Cells from Human Embryonic Stem Cells Promote Neural Tissue Integrity and Behavioral Performance in A Rat Stroke Model

  • Han-Soo Kim
  • Seong-Mi Choi
  • Wonsuk Yang
  • Dae-Sung Kim
  • Dongjin R. Lee
  • Sung-Rae ChoEmail author
  • Dong-Wook KimEmail author
Article

Abstract

Recently, cell-based therapy has been highlighted as an alternative to treating ischemic brain damage in stroke patients. The present study addresses the therapeutic potential of polysialic acid-neural cell adhesion molecule (PSA-NCAM)-positive neural precursor cells (NPCPSA-NCAM+) derived from human embryonic stem cells (hESCs) in a rat stroke model with permanent middle cerebral artery occlusion. Data showed that rats transplanted with NPCPSA-NCAM+ are superior to those treated with phosphate buffered saline (PBS) or mesenchymal stem cells (MSCs) in behavioral performance throughout time points. In order to investigate its underlying events, immunohistochemical analysis was performed on rat ischemic brains treated with PBS, MSCs, and NPCPSA-NCAM+. Unlike MSCs, NPCPSA-NCAM+ demonstrated a potent immunoreactivity against human specific nuclei, doublecortin, and Tuj1 at day 26 post-transplantation, implying their survival, differentiation, and integration in the host brain. Significantly, NPCPSA-NCAM+ evidently lowered the positivity of microglial ED-1 and astrocytic GFAP, suggesting a suppression of adverse glial activation in the host brain. In addition, NPCPSA-NCAM+ elevated α-SMA+ immunoreactivity and the expression of angiopoietin-1 indicating angiogenic stimulation in the host brain. Taken together, the current data demonstrate that transplanted NPCPSA-NCAM+ preserve brain tissue with reduced infarct size and improve behavioral performance through actions encompassing anti-reactive glial activation and pro-angiogenic activity in a rat stroke model. In conclusion, the present findings support the potentiality of NPCPSA-NCAM+ as the promising source in the development of cell-based therapy for neurological diseases including ischemic stroke.

Keywords

PSA-NCAM Neural precursor cells Human embryonic stem cells Pluripotent stem cells Mesenchymal stem cells Ischemic stroke 

Notes

Acknowledgments

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (2010-0020408; 2012M3A9B4028631; 2012M3A9B4028639; 2012M3A9C7050126), and by a grant (A1202254) of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. Seong-Mi Choi and Wonsuk Yang equally contributed to this work.

Conflict of Interest

The authors declare no potential conflicts of interest in this study.

Supplementary material

12015_2014_9535_MOESM1_ESM.pptx (69 kb)
Fig. S1 The expression levels of rat and human neurotrophic factors in ischemic brain were assessed using RT-PCR at day 26 after transplantation with NPCPSA-NCAM+”, respectively, MSCs or PBS. A representative RT-PCR amplification of neurotrophic factors and the quantification of GAPDH-normalized mRNA levels to that of sham controls (baseline) (n = 3 per group) are shown. Values are mean ± S.E.M. *P < 0.05 when compared to those of PBS group.(PPTX 69.1kb)

References

  1. 1.
    Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98, 1076–1084.PubMedCrossRefGoogle Scholar
  2. 2.
    Chen, J., Li, Y., Katakowski, M., et al. (2003). Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. Journal of Neuroscience Research, 73, 778–786.PubMedCrossRefGoogle Scholar
  3. 3.
    Kopen, G. C., Prockop, D. J., & Phinney, D. G. (1999). Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proceedings of the National Academy of Sciences, 96, 10711–10716.CrossRefGoogle Scholar
  4. 4.
    Liu, J., Han, D., Wang, Z., et al. (2013). Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy, 15, 185–191.PubMedCrossRefGoogle Scholar
  5. 5.
    Bhasin, A., Srivastava, M. V., Mohanty, S., Bhatia, R., Kumaran, S. S., & Bose, S. (2013). Stem cell therapy: a clinical trial of stroke. Clinical Neurology and Neurosurgery, 115, 1003–1008.PubMedCrossRefGoogle Scholar
  6. 6.
    Bae, K. S., Park, J. B., Kim, H. S., Kim, D. S., Park, D. J., & Kang, S. J. (2011). Neuron-like differentiation of bone marrow-derived mesenchymal stem cells. Yonsei Medical Journal, 52, 401–412.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Cho, S. R., Kim, Y. R., Kang, H. S., et al. (2009). Functional recovery after the transplantation of neurally differentiated mesenchymal stem cells derived from bone barrow in a rat model functional recovery after the transplantation of spinal cord injury. Cell Transplantion, 18, 1359–1368.CrossRefGoogle Scholar
  8. 8.
    Capone, C., Frigerio, S., Fumagalli, S., et al. (2007). Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment. PLoS ONE, 7, e373.CrossRefGoogle Scholar
  9. 9.
    Kim, D. S., Lee, D. R., Kim, H. S., et al. (2012). Highly pure and expandable PSA-NCAM-positive neural precursors from human ESC and iPSC-derived neural rosettes. PLoS ONE, 7, e39715.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Honmou, O., Onodera, R., Sasaki, M., Waxman, S. G., & Kocsis, J. D. (2012). Mesenchymal stem cells: therapeutic outlook for stroke. Trends in Molecular Medicine, 18, 292–297.PubMedCrossRefGoogle Scholar
  11. 11.
    Kim, D. S., Lee, J. S., Leem, J. W., et al. (2010). Robust enhancement of neural differentiation from human ES and iPS cells regardless of their innate difference in differentiation propensity. Stem Cell Reviews and Reports, 6, 270–281.PubMedCrossRefGoogle Scholar
  12. 12.
    Colle, L. M., Holmes, L. J., & Pappius, H. M. (1986). Correlation between behavioral status and cerebral glucose utilization in rats following freezing lesion. Brain Research, 397, 27–36.PubMedCrossRefGoogle Scholar
  13. 13.
    Borlongan, C. V., Cahill, D. W., & Sanberg, P. R. (1995). Locomotor and passive avoidance deficits following occlusion of the middle cerebral artery. Physiology & Behavior, 58, 909–917.CrossRefGoogle Scholar
  14. 14.
    Grabowski, M., Brundin, P., & Johansson, B. B. (1993). Paw-reaching, sensorimotor, and rotational behavior after brain infarction in rats. Stroke, 24, 889–895.PubMedCrossRefGoogle Scholar
  15. 15.
    Gonzalez, F. F., McQuillen, P., Mu, D., et al. (2007). Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Developmental Neuroscience, 29, 321–330.PubMedCrossRefGoogle Scholar
  16. 16.
    Ding, D. C., Shyu, W. C., & Lin, S. Z. (2011). Mesenchymal stem cells. Cell Transplantation, 20, 5–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Chang, D. J., Oh, S. H., Lee, N., et al. (2013). Contralaterally transplanted human embryonic stem cell-derived neural precursor cells (ENStem-A) migrate and improve brain functions in stroke-damaged rats. Experimental and Molecular Medicine, 45, e53.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Mine, Y., Tatarishvili, J., Oki, K., Monni, E., Kokaia, Z., & Lindvall, O. (2013). Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats. Neurobiology of Disease, 52, 191–203.PubMedCrossRefGoogle Scholar
  19. 19.
    Michel-Monigadon, D., Brachet, P., Neveu, I., & Naveilhan, P. (2011). Immunoregulatory properties of neural stem cells. Immunotherapy, 3, 39–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Rogers, D. C., Campbell, C. A., Stretton, J. L., & Mackay, K. B. (1997). Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke, 28, 2060–2065.PubMedCrossRefGoogle Scholar
  21. 21.
    Li, T., Pang, S., Yu, Y., Wu, X., Guo, J., & Zhang, S. (2013). Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke. Brain, 136(Pt 12), 3578–3588.PubMedCrossRefGoogle Scholar
  22. 22.
    Pekny, M., Wilhelmsson, U., & Pekna, M. (2014). The dual role of astrocyte activation and reactive gliosis. Neuroscience Letter, 565C, 30–38.CrossRefGoogle Scholar
  23. 23.
    Huang, L., Wu, Z. B., Zhuge, Q., et al. (2014). Glial scar formation occurs in the human brain after ischemic stroke. International Journal of Medical Sciences, 11, 344–348.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Tuttolomondo, A., Di Raimondo, D., di Sciacca, R., Pinto, A., & Licata, G. (2008). Inflammatory cytokines in acute ischemic stroke. Current Pharmaceutical Design, 14, 3574–3589.PubMedCrossRefGoogle Scholar
  25. 25.
    Chang, D. J., Lee, N., Park, I. H., et al. (2013). Therapeutic potential of human induced pluripotent stem cells in experimental stroke. Cell Transplantation, 22, 1427–1440.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang, P., Li, J., Liu, Y., et al. (2011). Human embryonic neural stem cell transplantation increases subventricular zone cell proliferation and promotes peri-infarct angiogenesis after focal cerebral ischemia. Neuropathology, 31, 384–391.PubMedCrossRefGoogle Scholar
  27. 27.
    Maurer, M. H., Thomas, C., Bürgers, H. F., & Kuschinsky, W. (2007). Transplantation of adult neural progenitor cells transfected with vascular endothelial growth factor rescues grafted cells in the rat brain. International Journal of Biological Science, 4, 1–7.Google Scholar
  28. 28.
    Liu, J., Wang, Y., Akamatsu, Y., et al. (2014). Vascular remodeling after ischemic stroke: Mechanisms and therapeutic potentials. Progress in Neurobiology, 115C, 138–156.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Han-Soo Kim
    • 1
  • Seong-Mi Choi
    • 1
  • Wonsuk Yang
    • 1
  • Dae-Sung Kim
    • 1
  • Dongjin R. Lee
    • 1
    • 2
  • Sung-Rae Cho
    • 3
    Email author
  • Dong-Wook Kim
    • 1
    • 2
    Email author
  1. 1.Department of Physiology and Cell Therapy CenterYonsei University College of MedicineSeoulSouth Korea
  2. 2.Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulSouth Korea
  3. 3.Department and Research Institute of Rehabilitation MedicineYonsei University College of MedicineSeoulSouth Korea

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