The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells

Christopher J. Bissonnette, Ljuba Lyass, Bula J. Bhattacharyya, Abdelhak Belmadani, Richard J. Miller, John A. Kessler

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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. siRNAmediated 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.

Original languageEnglish (US)
Pages (from-to)802-811
Number of pages10
JournalStem Cells
Volume29
Issue number5
DOIs
StatePublished - May 2011

Keywords

  • Alzheimer's disease
  • Cell differentiation
  • Cholinergic fibers
  • Embryonic stem cell
  • Growth differentiation factor 2
  • Neural stem cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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