The Controlled Generation of Functional Basal Forebrain Cholinergic Neurons from Human Embryonic Stem Cells§

Authors


  • Author contributions: C.B.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; L.L.: provision of study material; B.B.: collection and assembly of data; A.B.: collection of data; R.M.: conception and design; J.K.: conception and design, financial support, data analysis and interpretation, final approval of manuscript.

  • First published online in STEM CELLS EXPRESS February 13, 2011.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

Abstract

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 (hESCs) into BFCN would be a significant step toward 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 hESCs 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. STEM CELLS 2011;29:802–811

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