Region‐specific differentiation of embryonic stem cell‐derived neural progenitor transplants into the adult mouse hippocampus following seizures

Abstract

Embryonic stem (ES) cells can generate neural progenitors and neurons in vitro and incorporate into the adult central nervous system (CNS) following transplantation, suggesting their therapeutic potential for treating neurological disorders. However, our understanding of the conditions that direct ES-derived neural progenitor (ESNP) migration and differentiation within different regions of the adult CNS is incomplete. Rodents treated with the chemoconvulsant kainic acid (KA) experience seizures and display hippocampal sclerosis, as well as enhanced hippocampal neurogenesis, similar to pathological findings in patients with temporal lobe epilepsy (TLE). To examine the potential for ESNPs to incorporate into the adult hippocampus and differentiate into hippocampal neurons or glia following seizure-induced damage, we compared the fates of ESNPs after they were transplanted into the CA3 region or fimbria 1 week following KA-induced seizures. After 4-8 weeks, ESNPs grafted into the CA3 region had migrated to the dentate gyrus (DG), where a small subset adopted neural stem cell fates and continued to proliferate, based on bromodeoxyuridine uptake. Others differentiated into neuroblasts or dentate granule neurons. In contrast, most ESNPs transplanted into the fimbria migrated extensively along existing fiber tracts and differentiated into oligodendrocytes or astrocytes. Hippocampal grafts in mice not subjected to seizures displayed a marked tendency to form tumors, and this effect was more pronounced in the DG than in the fimbria. Taken together, these data suggest that seizures induce molecular changes in the CA3 region and DG that promote region-specific neural differentiation and suppress tumor formation.

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

“…Prior attempts to use transplantation to modify stimulation-induced electrical afterdischarge demonstrated modest suppression by using: (i) immortalized cells engineered to produce GABA (7,9), (ii) embryonic stem cells modified to release adenosine (4), (iii) fetal ''GABA-rich'' tissue (19,20), or (iv) viral vectors engineered to produce glial cell line-derived neurotrophic factor (21), neuropeptide Y (22), or galanin (23,24). In addition, a reduction in behavioral seizures in rat models of acquired epilepsy was observed after grafting of embryonic stem cells (25), striatal precursor cells (26), or fetal hippocampal cells (27). These cell transplantation procedures primarily transplanted into the substantia nigra or hippocampus, relied exclusively on assessment of stimulationevoked afterdischarge or behavioral observation, and often showed only transient effects.…”

Silk polymer-based adenosine release: Therapeutic potential for epilepsy

“…These range from electrical and magnetic stimulation [36][37][38][39], focal cooling [40], cell therapies [6,7,13,41,42], and gene therapies [43][44][45][46], to the ketogenic diet [47,48]. We recently established a neurochemical rationale for focal adenosine augmentation therapies (AATs).…”

Migration of Neurotrophic Factors-Secreting Mesenchymal Stem Cells Toward a Quinolinic Acid Lesion as Viewed by Magnetic Resonance Imaging

“…Moreover, the upregulation of migration was shown under the influence of brain-derived neurotrophic factor (BDNF) [23]. The migration phenomena are now harnessed in the stem cell research field, especially in the MRI context, and there are accumulating data that demonstrate how exogenous stem cells of various origins migrate in the CNS [7,8,24], and specifically toward QA-induced lesion [25].…”