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

doi:10.1016/j.stem.2009.08.019

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	409-419
Number of pages	11
Journal	Cell Stem Cell
Volume	5
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2009.08.019
State	Published - Oct 2 2009

Keywords

HUMDISEASE
STEMCELL

ASJC Scopus subject areas

Cell Biology
Molecular Medicine
Genetics

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10.1016/j.stem.2009.08.019

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Sacchetti, P., Sousa, K. M., Hall, A. C., Liste, I., Steffensen, K. R., Theofilopoulos, S., Parish, C. L., Hazenberg, C., Richter, L. Ä., Hovatta, O., Gustafsson, J. Å., & Arenas, E. (2009). Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells. Cell Stem Cell, 5(4), 409-419. https://doi.org/10.1016/j.stem.2009.08.019

@article{5b4aae00c5104fa89a710bfd24ceb2d0,

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

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.",

keywords = "HUMDISEASE, STEMCELL",

author = "Paola Sacchetti and Sousa, {Kyle M.} and Hall, {Anita C.} and Isabel Liste and Steffensen, {Knut R.} and Spyridon Theofilopoulos and Parish, {Clare L.} and Carin Hazenberg and Richter, {Lars {\"A}hrlund} and Outti Hovatta and Gustafsson, {Jan {\AA}ke} and Ernest Arenas",

note = "Funding Information: The authors are grateful to Drs. Magdalena G{\"o}tz, Weimin Zhong, and Fran{\c c}ois 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 S{\"o}derlund 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.{\"A}.R., and J.-{\AA}.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.-{\AA}.G. is shareholder and consultant of KaroBio AB and was supported by a grant from KaroBio AB. ",

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doi = "10.1016/j.stem.2009.08.019",

language = "English (US)",

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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.

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

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