TY - JOUR
T1 - Human embryonic stem cell derived astrocytes mediate non-cell-autonomous neuroprotection through endogenous and drug-induced mechanisms
AU - Gupta, K.
AU - Patani, R.
AU - Baxter, P.
AU - Serio, A.
AU - Story, D.
AU - Tsujita, T.
AU - Hayes, J. D.
AU - Pedersen, R. A.
AU - Hardingham, G. E.
AU - Chandran, S.
N1 - Funding Information:
Acknowledgements. We thank Professor Michael Sporn for the gift of CDDOTFEA, Professor Jeff Johnson for comments on the manuscript, and Professor Masayuki Yamamoto of the University of Tsukuba (now University of Tohoku) for kindly providing Nrf2−/− mice. TT and JDH wish to thank the Association for International Cancer Research for their support (Grant 07-0074). This work was funded by the Evelyn Trust, Motor Neuron Disease Association, Medical Research Council, and the Wellcome Trust.
PY - 2012/5
Y1 - 2012/5
N2 - The glial environment is an important determinant of neuronal health in experimental models of neurodegeneration. Specifically, astrocytes have been shown, dependent on context, to be both injurious and protective. Human pluripotent stem cells offer a powerful new system to improve our understanding of the mechanisms underlying astrocyte-mediated neuroprotection. Here, we describe a human embryonic stem cell (HESC)-based system to assess the scope and mechanism of human astrocyte-mediated neuroprotection. We first report the generation of enriched and functional HESC-derived astrocytes, by combining BMP-mediated Smad and LIF-mediated JAK-STAT signalling. These astrocytes promote the protection of HESC-derived neurons against oxidative insults. Moreover, their neuroprotective capacity can be greatly enhanced by treatment with the nuclear factor-erythroid 2-related factor 2 (Nrf2)-activating triterpenoid 1[2-Cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoroethylamide (CDDO TFEA). Activation of the transcription factor Nrf2 in human astrocytes by CDDO TFEA treatment induced expression of the glutamate-cysteine ligase (GCL) catalytic subunit, leading to enhanced GCL activity and glutathione production, and strong neuroprotection against H 2O 2. This enhanced neuroprotection was found to be dependent on astrocytic GCL activity, unlike the basal neuroprotection afforded by untreated astrocytes. Direct treatment of HESC-derived neurons with CDDO TFEA elicited no induction of Nrf2 target genes, nor any neuroprotection. Thus, human astrocytes can mediate neuroprotection through glutathione-dependent and glutathione-independent mechanisms, and represent a therapeutic target for human disorders associated with neuronal oxidative stress.
AB - The glial environment is an important determinant of neuronal health in experimental models of neurodegeneration. Specifically, astrocytes have been shown, dependent on context, to be both injurious and protective. Human pluripotent stem cells offer a powerful new system to improve our understanding of the mechanisms underlying astrocyte-mediated neuroprotection. Here, we describe a human embryonic stem cell (HESC)-based system to assess the scope and mechanism of human astrocyte-mediated neuroprotection. We first report the generation of enriched and functional HESC-derived astrocytes, by combining BMP-mediated Smad and LIF-mediated JAK-STAT signalling. These astrocytes promote the protection of HESC-derived neurons against oxidative insults. Moreover, their neuroprotective capacity can be greatly enhanced by treatment with the nuclear factor-erythroid 2-related factor 2 (Nrf2)-activating triterpenoid 1[2-Cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoroethylamide (CDDO TFEA). Activation of the transcription factor Nrf2 in human astrocytes by CDDO TFEA treatment induced expression of the glutamate-cysteine ligase (GCL) catalytic subunit, leading to enhanced GCL activity and glutathione production, and strong neuroprotection against H 2O 2. This enhanced neuroprotection was found to be dependent on astrocytic GCL activity, unlike the basal neuroprotection afforded by untreated astrocytes. Direct treatment of HESC-derived neurons with CDDO TFEA elicited no induction of Nrf2 target genes, nor any neuroprotection. Thus, human astrocytes can mediate neuroprotection through glutathione-dependent and glutathione-independent mechanisms, and represent a therapeutic target for human disorders associated with neuronal oxidative stress.
KW - Nrf2
KW - astrocytes
KW - glutathione
KW - human stem cells
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UR - http://www.scopus.com/inward/citedby.url?scp=84859617138&partnerID=8YFLogxK
U2 - 10.1038/cdd.2011.154
DO - 10.1038/cdd.2011.154
M3 - Article
C2 - 22095276
AN - SCOPUS:84859617138
VL - 19
SP - 779
EP - 787
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 5
ER -
