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Abstract
This review article discusses recent progress on the use of teratocarcinoma-derived
Ntera2/D1 neuron-like cells (NT2N cells, also called hNT cells) as graft source for
cell transplantation in stroke. Laboratory evidence has demonstrated the therapeutic
potential of NT2N cells in stroke therapy. Phase I and II clinical trials have shown
the cells' feasibility, safety and tolerability profiles in stroke patients. Despite
these novel features of NT2N cells, the transplantation regimen remains to be optimized.
Moreover, determining the mechanisms underlying the grafts' beneficial effects, specifically
demonstrating functional synaptic connections between host brain and NT2N cell grafts,
warrants further examination. The major limiting factor for initiating a large clinical
trial is the cells' highly potent proliferative property due to their cancerous origin,
thereby raising the concern that these cells may revert to a neoplastic state over
time after transplantation. To this end, we explored a proof-of-concept "retroviral"
strategy to further establish the post-mitotic status of NT2N cells by transfecting
these cells with the transcription factor Nurr1, in addition to the standard treatment
with retinoic acid and mitotic inhibitors. This new cell line NT2N.Nurr1 displays
an expedited neuronal commitment and secretes a high level of the neurotrophic factor
glial cell line-derived neurotrophic factor (GDNF), and when transplanted into the
rodent stroke brain expressed neuronal phenotype and reduced behavioral impairments
which are comparable, if not more robust, than those produced by NT2N cells. Such
highly potent neuronal lineage commitment and neurotrophic factor secretory function
of NT2.Nurr1 cells make them an appealing graft source for transplantation therapy.