Regenerative Medicine

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Medial Ganglionic Eminence-Derived Neural Stem Cell Grafts Ease Spontaneous Seizures and Restore GDNF Expression in a Rat Model of Chronic Temporal Lobe Epilepsy†‡§

  1. Ben Waldau1,2,
  2. Bharathi Hattiangady1,2,
  3. Ramkumar Kuruba1,2,
  4. Ashok K. Shetty1,2,¶,*

Article first published online: 18 MAY 2010

DOI: 10.1002/stem.446

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 7, pages 1153–1164, July 2010

Additional Information

How to Cite

Waldau, B., Hattiangady, B., Kuruba, R. and Shetty, A. K. (2010), Medial Ganglionic Eminence-Derived Neural Stem Cell Grafts Ease Spontaneous Seizures and Restore GDNF Expression in a Rat Model of Chronic Temporal Lobe Epilepsy. STEM CELLS, 28: 1153–1164. doi: 10.1002/stem.446

Author Information

  1. 1

    Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, North Carolina, USA

  2. 2

    Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham, North Carolina, USA

  1. Telephone: (919)-286-0411, Ext. 7096; Fax: (919)-286-4662

*Division of Neurosurgery, Department of Surgery, Duke University Medical Center, DUMC Box 3807, Durham, North Carolina 27710, USA

  1. †

    Author contributions: B.W.: design, collection, assembly, analyses and interpretation of data, manuscript writing; B.H.: design, collection, assembly, analyses and interpretation of data, final approval of manuscript; R.K.: collection, assembly and analyses of data, final approval of manuscript; A.K.S.: conception, design, collection, assembly, analyses and interpretation of data, manuscript writing, and financial support.

  2. ‡

    First published online in STEM CELLS EXPRESS May 18, 2010.

  3. §

    Disclosure of potential conflicts of interest is found at the end of this article.

  4. Telephone: (919)-286-0411, Ext. 7096; Fax: (919)-286-4662

Publication History

  1. Issue published online: 20 JUL 2010
  2. Article first published online: 18 MAY 2010
  3. Manuscript Accepted: 7 MAY 2010
  4. Manuscript Received: 19 NOV 2009

Funded by

  • National Institute of Neurological Disorders and Stroke. Grant Number: RO1 NS054780
  • Department of Veterans Affairs
  • Ben Waldau was partially supported by the 2007 Congress of Neurological Surgeons (CNS) Translational/Basic Science Resident Research fellowship

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Keywords:

  • Neural stem cell therapy;
  • Chronic epilepsy;
  • Glial-derived neurotrophic factor;
  • Hippocampal neurogenesis;
  • Medial ganglionic eminence;
  • Learning and memory;
  • Spontaneous seizures

Abstract

Nearly 30% of patients with mesial temporal lobe epilepsy (TLE) are resistant to treatment with antiepileptic drugs. Neural stem cell (NSC) grafting into the hippocampus could offer an alternative therapy to hippocampal resection in these patients. As TLE is associated with reduced numbers of inhibitory gamma-amino butyric acid (GABA)-ergic interneurons and astrocytes expressing the anticonvulsant glial-derived neurotrophic factor (GDNF) in the hippocampus, we tested the hypothesis that grafting of NSCs that are capable of adding new GABA-ergic interneurons and GDNF-expressing astrocytes into the epileptic hippocampus restrains spontaneous recurrent motor seizures (SRMS) in chronic TLE. We grafted NSCs expanded in vitro from embryonic medial ganglionic eminence (MGE) into hippocampi of adult rats exhibiting chronic TLE with cognitive impairments. NSC grafting reduced frequencies of SRMS by 43% and stage V seizures by 90%. The duration of individual SRMS and the total time spent in seizures were reduced by 51 and 74%, respectively. Grafting did not improve the cognitive function however. Graft-derived cells (equivalent to ∼28% of injected cells) were observed in various layers of the epileptic hippocampus where they differentiated into NeuN+ neurons (13%), S-100β+ astrocytes (57%), and NG2+ oligodendrocyte-progenitors (3%). Furthermore, among graft-derived cells, 10% expressed GABA and 50% expressed GDNF. Additionally, NSC grafting restored GDNF in a vast majority of the hippocampal astrocytes but had no effect on neurogenesis. Thus, MGE-NSC therapy is efficacious for diminishing SRMS in chronic TLE. Addition of new GABA-ergic neurons and GDNF+ cells, and restoration of GDNF in the hippocampal astrocytes may underlie the therapeutic effect of MGE-NSC grafts. STEM CELLS 2010;28:1153–1164

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