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Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):287-296. doi: 10.1073/pnas.1814185115. Epub 2018 Dec 17.

Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration.

Upadhya D1,2,3,4, Hattiangady B1,3,4, Castro OW2,3,4, Shuai B1,2,3,4, Kodali M1,2,3,4, Attaluri S1,2,3,4, Bates A1,2,3,4, Dong Y5,6, Zhang SC5,6, Prockop DJ7,2,3, Shetty AK7,2,3,4.

Author information

1
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76502.
2
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX 77845.
3
Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX 77845.
4
Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX 76504.
5
Waisman Center, Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706.
6
Waisman Center, Department of Neurology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706.
7
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76502; shetty@medicine.tamhsc.edu prockop@medicine.tamhsc.edu.

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.

KEYWORDS:

EEG recordings; GABA-ergic progenitors; cognition and mood; medial ganglionic eminence; temporal lobe epilepsy

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