西亚试剂：The Controlled Generation of Functional Basal Forebrain Cho

The Controlled Generation of Functional Basal Forebrain Cholinergic Neurons from Human Embryonic Stem Cells
Christopher John Bissonnette1, Ljuba Lyass1, Bula J Bhattacharyya2, Abdelhak Belmadani2, Richard J Miller2, John A Kessler1,*,?

An early substantial loss of basal forebrain cholinergic neurons [BFCN] is a constant feature of Alzheimer's disease and is associated with deficits in spatial learning and memory. The ability to selectively control the differentiation of human embryonic stem cells [hESC] into BFCN would be a significant step towards a cell replacement therapy. We demonstrate here a method for the derivation of a predominantly pure population of BFCN from hESC cells using diffusible ligands present in the forebrain at developmentally relevant time periods. Overexpression of two relevant human transcription factors in hESC-derived neural progenitors also generates BFCN. These neurons express only those markers characteristic of BFCN, generate action potentials, and form functional cholinergic synapses in murine hippocampal slice cultures. siRNA-mediated knockdown of the transcription factors blocks BFCN generation by the diffusible ligands, clearly demonstrating the factors both necessary and sufficient for the controlled derivation of this neuronal population. The ability to selectively control the differentiation of human embryonic stem cells [hESC] into BFCN is a significant step both for understanding mechanisms regulating BFCN lineage commitment and for the development of both cell-transplant-mediated therapeutic interventions for Alzheimer's disease and high throughput screening for agents that promote BFCN survival.

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