Conditionally immortalized, multipotential and multifunctional neural stemcell lines as an approach to clinical transplantation

Experiments are described using rats with two kinds of brain damage and con sequent cognitive deficit tin the Morris water maze, three-door runway, and radial maze): I) ischemic damage to the CAI hippocampal cell field after f our-vessel occlusion (4VO), and 2) damage to the forebrain cholinergic proj ection system by local injection of excitotoxins to the nuclei of origin or prolonged ethanol administration. Cell suspension grafts derived From prim ary fetal brain tissue display a stringent requirement for homotypical cell replacement in the 4VO model: cells from the embryonic day (E)18-19 CAI hi ppocampal subfield, but not from CA3 or dentate gyrus or from E16 basal for ebrain (cholinergic rich) led to recovery of cognitive function. After dama ge to the cholinergic system, conversely, recovery of function was seen wit h cell suspension grafts fi om E16 basal forebrain or cholinergic-rich E14 ventral mesencephalon, but not with implants of hippocampal tissue. These t wo models therefore provided a test of multifunctionality for a clonal line of conditionally immortalized neural stem cells, MHP36, derived from the E 14 "immortomouse" hippocampal anlage. implanted above the damaged CAI cell field in 4VO-treated adult rats, these cells (multipotential in vitro) migr ated to the damaged area, reconstituted the gross morphology of the CAI pyr amidal layer, took up br,th neuron;ll and glial phenotypes, and gave rise t o cognitive recovery. Similar recovery of function and restoration of speci es-typical morphology was observed when MHP36 cells were implanted into mar mosets with excitotoxic CAI damage. MHP36 implants led to recovery of cogni tive function also in two experiments with rats with excitotoxic damage to the cholinergic system damage, either unilaterally in the nucleus basalis o r bilaterally in both the nucleus basalis and the medial septal area. Thus, MHP36 cells are both multipotent (able to take up multiple cellular phenot ypes) and multifunctional table to repair diverse types of brain damage).