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Contributed by Darwin J. Prockop, November 6, 2018 (sent for review August 19, 2018; reviewed by Detlev Boison and William P. Gray)
Significance
This study provides evidence that human induced pluripotent stem cell (hiPSC)-derived medial ganglionic eminence (MGE) cell grafting into the hippocampus after status epilepticus can greatly reduce the frequency of spontaneous seizures in the chronic phase through both antiepileptogenic and antiepileptic effects. The antiepileptogenic changes comprised reductions in host interneuron loss, abnormal neurogenesis, and aberrant mossy fiber sprouting, whereas the antiepileptic effects were evident from an increased occurrence of seizures after silencing of graft-derived interneurons. Additional curative impacts of grafting comprised improved cognitive and mood function. The results support the application of autologous human MGE cell therapy for temporal lobe epilepsy. Autologous cell therapy is advantageous as such a paradigm can avoid immune suppression and promote enduring graft–host integration.
Abstract
Medial ganglionic eminence (MGE)-like interneuron precursors derived from human induced pluripotent stem cells (hiPSCs) are ideal for developing patient-specific cell therapy in temporal lobe epilepsy (TLE). However, their efficacy for alleviating spontaneous recurrent seizures (SRS) or cognitive, memory, and mood impairments has never been tested in models of TLE. Through comprehensive video- electroencephalographic recordings and a battery of behavioral tests in a rat model, we demonstrate that grafting of hiPSC-derived MGE-like interneuron precursors into the hippocampus after status epilepticus (SE) greatly restrained SRS and alleviated cognitive, memory, and mood dysfunction in the chronic phase of TLE. Graft-derived cells survived well, extensively migrated into different subfields of the hippocampus, and differentiated into distinct subclasses of inhibitory interneurons expressing various calcium-binding proteins and neuropeptides. Moreover, grafting of hiPSC-MGE cells after SE mediated several neuroprotective and antiepileptogenic effects in the host hippocampus, as evidenced by reductions in host interneuron loss, abnormal neurogenesis, and aberrant mossy fiber sprouting in the dentate gyrus (DG). Furthermore, axons from graft-derived interneurons made synapses on the dendrites of host excitatory neurons in the DG and the CA1 subfield of the hippocampus, implying an excellent graft–host synaptic integration. Remarkably, seizure-suppressing effects of grafts were significantly reduced when the activity of graft-derived interneurons was silenced by a designer drug while using donor hiPSC-MGE cells expressing designer receptors exclusively activated by designer drugs (DREADDs). These results implied the direct involvement of graft-derived interneurons in seizure control likely through enhanced inhibitory synaptic transmission. Collectively, the results support a patient-specific MGE cell grafting approach for treating TLE.
- EEG recordings
- cognition and mood
- GABA-ergic progenitors
- medial ganglionic eminence
- temporal lobe epilepsy
Footnotes
↵1Present address: Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka, India.
↵2Present address: Institute Biological Sciences and Health, Federal University of Alagoas, Maceio, AL 57072-970, Brazil.
↵3S.-C.Z., D.J.P., and A.K.S. contributed equally to this work.
- ↵4To whom correspondence may be addressed. Email: shetty{at}medicine.tamhsc.edu or prockop{at}medicine.tamhsc.edu.
Author contributions: D.U., D.J.P., and A.K.S. designed research; D.U., B.H., O.W.C., B.S., M.K., S.A., A.B., Y.D., and A.K.S. performed research; D.U., B.H., O.W.C., S.-C.Z., and A.K.S. analyzed data; and D.U., S.-C.Z., D.J.P., and A.K.S. wrote the paper.
Reviewers: D.B., Legacy Research Institute; and W.P.G., Institute of Psychological Medicine and Clinical Neurosciences.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1814185115/-/DCSupplemental.
- Copyright © 2019 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration
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