TY - JOUR
T1 - Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells
AU - Sacchetti, Paola
AU - Sousa, Kyle M.
AU - Hall, Anita C.
AU - Liste, Isabel
AU - Steffensen, Knut R.
AU - Theofilopoulos, Spyridon
AU - Parish, Clare L.
AU - Hazenberg, Carin
AU - Richter, Lars Ährlund
AU - Hovatta, Outti
AU - Gustafsson, Jan Åke
AU - Arenas, Ernest
N1 - Funding Information:
The authors are grateful to Drs. Magdalena Götz, Weimin Zhong, and François Guillemot for their invaluable comments and critical support of this work. We also thank Helder Andre for comments and suggestions on the manuscript, Dr. Ruani Fernando for invaluable discussion and technical help on histology and imaging, and Johnny Söderlund for technical assistance. This work was supported by the Michael J. Fox Foundation, Swedish Foundation for Strategic Research (INGVAR and CEDB), European Union (Strokemap, NeuroStemCell), Karolinska Institutet, Petrus and Augusta Hedlunds Foundation, Swedish Research Council (VR2008:3287 and DBRM), and Norwegian Research Council to E.A., and grants from VR to O.H., L.Ä.R., and J.-Å.G. E.A. was supported by Swedish Royal Academy of Sciences and Knut and Alice Wallenberg Foundation, P.S. was supported by Norwegian Research Council, and A.C.H. was supported by Human Frontiers Science Program. C.L.P. was supported by an Australian National Health and Medical Research Council (NHMRC) CJ Martin Fellowship and NHMRC Career Development Award. J.-Å.G. is shareholder and consultant of KaroBio AB and was supported by a grant from KaroBio AB.
PY - 2009/10/2
Y1 - 2009/10/2
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - STEMCELL
UR - http://www.scopus.com/inward/record.url?scp=70349309626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349309626&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2009.08.019
DO - 10.1016/j.stem.2009.08.019
M3 - Article
C2 - 19796621
SN - 1934-5909
VL - 5
SP - 409
EP - 419
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 4
ER -