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

Abstract

SignificanceThis 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.

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

“…Six hours after SE, animals in both naïve and SE groups underwent intracardiac perfusions with 4% paraformaldehyde. The brains were dissected, post-fixed in 4% paraformaldehyde overnight, and processed for sectioning using a cryostat [52][53][54][55][56]. Thirty micrometer-thick coronal sections were cut through the entire forebrain and collected serially in 24-well plates containing the phosphate buffer.…”

“…Optical Z-sections (1-µm thick) were sampled from different forebrain regions using a Nikon confocal microscope [53][54][55][56]. Z-stacks were captured from three different fields in every region of the forebrain for every marker analyzed in the study.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…Cellular therapies, especially with stem cells of different regenerative capacities, have been trialed in neurological disorders with chronic loss of specific cell types, such as Parkinson disease and Alzheimer disease, as well as brain injury associated with ongoing neurodegeneration such as stroke and TBI . Such therapies have also shown promising outcomes in epilepsy models administering the stem cells programmed to differentiate into GABAergic interneurons to counter the excessive network excitability . Genetically modified cells have also been injected into the brain to continuously deliver different neuropeptides or other molecules with antiepileptic potential and have shown positive outcomes .…”

“…96 Such therapies have also shown promising outcomes in epilepsy models administering the stem cells programmed to differentiate into GABAergic interneurons to counter the excessive network excitability. 97,98 Genetically modified cells have also been injected into the brain to continuously deliver different neuropeptides or other molecules with antiepileptic potential and have shown positive outcomes. 99,100 In addition, different types of stem cells, such as MSCs (multipotent cells of stromal origin) and neural stem cells (multipotent cells with the capacity to generate into neurons and glial cells), have been observed to interact with the host cells by the exchange of trophic growth factors and modulation of immune response.…”

Progress of Induced Pluripotent Stem Cell Technologies to Understand Genetic Epilepsy

“…Following this preliminary work, Upadhya and collaborators performed iPSCs-derived neural cell grafts into the hippocampus of a standard rat model of chronic TLE [111], i.e., the intra-hippocampal injection of kainic acid to induce status epilepticus and trigger spontaneous recurrent seizures. They further develop methods to improve the in vivo differentiation and functional integration of iPSC neurons by using iPSC-derived MGE-like interneuron precursors [112]. The efficient differentiation of iPSC-engrafted cells into GABAergic neurons after status epilepticus preserved the local inhibitory circuitry of the hippocampus and mitigated the progression of status epilepticus-induced injury.…”