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Suzuki, Sasaki, Kocsis , Honmou , et. al. Sapporo Medical University, Japan, Yale Medical School

Bilateral Cortical H yperactivity D etected B y fMRI Associates With I mproved M otor F unction F ollowing I ntravenous I nfusion of M esenchymal Stem C ells in a Rat S troke M odel. Suzuki, Sasaki, Kocsis , Honmou , et. al. Sapporo Medical University, Japan, Yale Medical School

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Suzuki, Sasaki, Kocsis , Honmou , et. al. Sapporo Medical University, Japan, Yale Medical School

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  1. Bilateral Cortical Hyperactivity Detected By fMRI Associates With Improved Motor Function Following Intravenous Infusion of Mesenchymal Stem Cells in a Rat Stroke Model Suzuki, Sasaki, Kocsis, Honmou, et. al. Sapporo Medical University, Japan, Yale Medical School Brain Research 2013 Kate Halabi ASR Junior November 22, 2013

  2. What are stem cells? INTRODUCTION • Pluripotent – can differentiate into any cell • Embryonic (ES) • Induced (iPS) • Somatic www.newsblog.mayoclinic.org www.vectorblog.org

  3. Uses of Stem Cells INTRODUCTION • Three main uses: • 1. Tissue regeneration • 2. Drug testing • 3. Disease modeling www.nature.com

  4. Mesenchymal Stem Cells (MSCs) INTRODUCTION • Multipotent stromal (connective/supportive) cells • From bone marrow • Largely quiescent, self-renew well www.neuro-zone.com www.omicsonline.org

  5. Stroke INTRODUCTION • Mostly ischemic – arterial clot  lack of blood flow • Causes tissue death due to lack of O2 • Leads to neurological damage • 800,000 people have strokes per year in the US, 130,000 deaths www.nature.com

  6. Problem • If mesenchymal stem cells are transfused intravenously into rats six hours after stroke, will they improve the functionality of the ischemic area as measured by fMRI and functional testing? Hypothesis • If mesenchymal stem cells are transfused intravenously into rats six hours after stroke, then functionality will be increased as evidenced by functional MRI and functional testing.

  7. Review of Literature • Johansson, B.B., 2011. Current trends in stroke rehabilitation. A review with focus on brain plasticity. Acta Neurol. Scand. 123, 147–159. • Honmou, O., Onodera, R., Sasaki, M., Waxman, S.G., Kocsis, J.D., 2012. Mesenchymal stem cells: therapeutic outlook for stroke. Trends Mol. Med. 18, 292–297. • Andres, R.H., Svendsen, C.N., Bliss, T.M., Steinberg, G.K., 2011. Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134, 1777–1789.

  8. Review of Literature • Chopp, M., Li, Y., 2009. Mechanisms underlying improved recovery of neurological function after stroke in the rodent after treatment with neurorestorative cell-based therapies. Stroke 40, S143–S145. • Neumann-Haefelin, T., Sun, G.H., Moseley, M.E., 2000. Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood-brain barrier damage, and edema formation.Stroke 31, 1965–1972, 1972-3. • Sasaki, M., Radtke, C., Honmou, O., Kocsis, J.D., 2009b. BDNF-hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. J. Neurosci. 29, 14932–14941.

  9. www.charlesstone.com

  10. Mesenchymal Stem Cell Isolation Methods and Materials • Bone marrow from femurs of anaesthetized adult rats • Placed onto cell culture plates • MSCs adhere to plastic and separate from other cells www.genengnews.com

  11. Stroke Induction Methods and Materials • 56 adult rats anesthetized • Surgical sutures with tips rounded by heating advanced from the external carotid to block the origin of the middle cerebral artery

  12. MSC Transfusion Into Rats Methods and Materials • Injected intravenously through the femoral vein 6 hours after stroke • 20 control rats only injected with medium • 36 experimental rats with 1ml MSCs and culture • All rats had daily cyclosporine A injections www.sciencelab.com

  13. Functional Magnetic Resonance Imaging (fMRI) Methods and Materials • Measures brain activity • Detects differences in blood oxygen levels in different parts of the brain • Blood oxygen levels represent activity in brain • Increase in deoxyhemoglobin indicates activity en.wikipedia.org

  14. Normal Rat Brain RESULTS • Method: fMRI • Electrical stimulation of left forepaw leads to signal on contralateral (right) side of brain

  15. Brain Recovery Over Time (fMRI) RESULTS

  16. RESULTS

  17. Treadmill Test RESULTS

  18. Hypothesis Supported DISCUSSION • Hypothesis: If mesenchymal stem cells are transfused intravenously into rats six hours after stroke, then functionality will be increased as evidenced by fMRI and functional testing. • Purpose was not to determine cause of repair • Hypothesize that it was due to neurotrophic factors, growth of blood vessels and immunomodulation

  19. Significance DISCUSSION • Even intravenous injection of MSCs facilitates repair • Demonstrates plasticity of the brain

  20. Errors DISCUSSION • Differences in severity of stroke hard to control • Size of artery varies • Hard to standardize procedure

  21. Future Work for the Field Conclusion • Fast moving field • Continue experimenting with stem cells for regeneration in animals • Eventually move to humans • Research with iPS cells

  22. My Future Work Conclusion • Flora Vaccarino, Yale School of Medicine • Continue to contact other potential mentors • SCISEF

  23. www.charlesstone.com

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