SFN Poster of the Year 2010

Awarded by ATS at Society for Neuroscience (SFN) November 14-17, 2010 • San Diego, CA

331.5/B19 Functional cholinergic neurons from human embryonic stem cells
Y Liu, R Krencik, H Liu, L Ma, X Zhang, S-C Zhang
featuring IT-16 mu p75-SAP (Poster; Monday, Nov. 15, 8:00 am – 9:00 am)

Basal forebrain cholinergic neurons play a critical role in regulating memory and cognition. Degeneration or dysfunction of these neurons is associated with neurological conditions including Alzheimer’s disease and dementia. In this study, we aimed at generating cholinergic neurons from human embryonic stem cells (hESCs) for therapeutic development. hESCs were first differentiated to primitive neuroepithelial cells in a chemically defined medium. In the presence of sonic hedgehog, over 97% of the differentiated cells became Nkx2.1-expressing ventral forebrain progenitors. These ventral progenitors further differentiated to cholinergic neurons with basal forebrain characteristics by expressing ChAT, VAChAT, FoxG1, Nkx2.1, Islet1, ßIII-tubulin, MAP2, P75, Synapsin but not GABA, Glutamate, or Mash2. The hESC-generated cholinergic neurons were electrophysiologically active in vitro. Following transplantation into the hippocampus of mice, in which cholinergic neurons in the medial septum were destroyed by IgG-P75-saporin, the grafted human cells produced large cholinergic neurons. The animals transplanted with cholinergic neurons demonstrated an improvement in learning and memory deficit. These results indicate that the human stem cell-generated cholinergic neurons are functional, thus providing a new source for drug discovery and cell therapy for neurological disorders that affect cholinergic neurons.