Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells

Paola Sacchetti, Kyle M. Sousa, Anita C. Hall, Isabel Liste, Knut R. Steffensen, Spyridon Theofilopoulos, Clare L. Parish, Carin Hazenberg, Lars Ährlund Richter, Outti Hovatta, Jan Åke Gustafsson, Ernest Arenas

    Research output: Contribution to journalArticlepeer-review

    122 Scopus citations

    Abstract

    Control over progenitor proliferation and neurogenesis remains a key challenge for stem cell neurobiology and a prerequisite for successful stem cell replacement therapies for neurodegenerative diseases like Parkinson's disease (PD). Here, we examined the function of two nuclear receptors, liver X receptors (Lxrα and β) and their ligands, oxysterols, as regulators of cell division, ventral midbrain (VM) neurogenesis, and dopaminergic (DA) neuron development. Deletion of Lxrs reduced cell cycle progression and VM neurogenesis, resulting in decreased DA neurons at birth. Activation of Lxrs with oxysterol ligands increased the number of DA neurons in mouse embryonic stem cells (ESCs) and in wild-type but not Lxrαβ-/- VM progenitor cultures. Likewise, oxysterol treatment of human ESCs (hESCs) during DA differentiation increased neurogenesis and the number of mature DA neurons, while reducing proliferating progenitors. Thus, Lxr ligands may improve current hESC replacement strategies for PD by selectively augmenting the generation of DA neurons.

    Original languageEnglish (US)
    Pages (from-to)409-419
    Number of pages11
    JournalCell Stem Cell
    Volume5
    Issue number4
    DOIs
    StatePublished - Oct 2 2009

    Keywords

    • HUMDISEASE
    • STEMCELL

    ASJC Scopus subject areas

    • Cell Biology
    • Molecular Medicine
    • Genetics

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