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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 1; pp. 287 - 296
• Main Authors: Upadhya, Dinesh, Hattiangady, Bharathi, Castro, Olagide W., Shuai, Bing, Kodali, Maheedhar, Attaluri, Sahithi, Bates, Adrian, Dong, Yi, Zhang, Su-Chun, Prockop, Darwin J., Shetty, Ashok K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.01.2019
• Series: PNAS Plus
• Subjects: Affect; Animal models; Animals; Axon sprouting; Axons; Biological Sciences; Brain; Brain - embryology; CA1 Region, Hippocampal - physiology; Calcium; Cognition; Cognitive ability; Comorbidity; Dendrites; Dentate gyrus; Dentate Gyrus - physiology; EEG; Epilepsy; Epilepsy - surgery; Epilepsy, Temporal Lobe - surgery; Grafting; Grafts; Hippocampus; Hippocampus - surgery; Humans; Immunosuppressive agents; Induced Pluripotent Stem Cells - transplantation; Integration; Interneurons; Male; Memory; Mood; Neurogenesis; Neuropeptides; Neuroprotection; Patients; PNAS Plus; Precursors; Proteins; Rats; Rats, Inbred F344; Receptors; Seizing; Seizures; Seizures - surgery; Status Epilepticus - surgery; Stem cell transplantation; Stem cells; Synapses; Synapses - physiology; Synaptic transmission; Temporal lobe; EEG recordings; temporal lobe epilepsy; cognition and mood; GABA-ergic progenitors; medial ganglionic eminence
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1814185115

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.