TY - JOUR
T1 - The Neurogenic Potential of Astrocytes Is Regulated by Inflammatory Signals
AU - Michelucci, Alessandro
AU - Bithell, Angela
AU - Burney, Matthew J.
AU - Johnston, Caroline E.
AU - Wong, Kee Yew
AU - Teng, Siaw Wei
AU - Desai, Jyaysi
AU - Gumbleton, Nigel
AU - Anderson, Gregory
AU - Stanton, Lawrence W.
AU - Williams, Brenda P.
AU - Buckley, Noel J.
N1 - Funding Information:
This work was supported by the Wellcome Trust, GIS, Fonds National de la Recherche Luxembourg (AFR PDR-09-003).
Publisher Copyright:
© 2015, The Author(s).
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Although the adult brain contains neural stem cells (NSCs) that generate new neurons throughout life, these astrocyte-like populations are restricted to two discrete niches. Despite their terminally differentiated phenotype, adult parenchymal astrocytes can re-acquire NSC-like characteristics following injury, and as such, these ‘reactive’ astrocytes offer an alternative source of cells for central nervous system (CNS) repair following injury or disease. At present, the mechanisms that regulate the potential of different types of astrocytes are poorly understood. We used in vitro and ex vivo astrocytes to identify candidate pathways important for regulation of astrocyte potential. Using in vitro neural progenitor cell (NPC)-derived astrocytes, we found that exposure of more lineage-restricted astrocytes to either tumor necrosis factor alpha (TNF-α) (via nuclear factor-κB (NFκB)) or the bone morphogenetic protein (BMP) inhibitor, noggin, led to re-acquisition of NPC properties accompanied by transcriptomic and epigenetic changes consistent with a more neurogenic, NPC-like state. Comparative analyses of microarray data from in vitro-derived and ex vivo postnatal parenchymal astrocytes identified several common pathways and upstream regulators associated with inflammation (including transforming growth factor (TGF)-β1 and peroxisome proliferator-activated receptor gamma (PPARγ)) and cell cycle control (including TP53) as candidate regulators of astrocyte phenotype and potential. We propose that inflammatory signalling may control the normal, progressive restriction in potential of differentiating astrocytes as well as under reactive conditions and represent future targets for therapies to harness the latent neurogenic capacity of parenchymal astrocytes.
AB - Although the adult brain contains neural stem cells (NSCs) that generate new neurons throughout life, these astrocyte-like populations are restricted to two discrete niches. Despite their terminally differentiated phenotype, adult parenchymal astrocytes can re-acquire NSC-like characteristics following injury, and as such, these ‘reactive’ astrocytes offer an alternative source of cells for central nervous system (CNS) repair following injury or disease. At present, the mechanisms that regulate the potential of different types of astrocytes are poorly understood. We used in vitro and ex vivo astrocytes to identify candidate pathways important for regulation of astrocyte potential. Using in vitro neural progenitor cell (NPC)-derived astrocytes, we found that exposure of more lineage-restricted astrocytes to either tumor necrosis factor alpha (TNF-α) (via nuclear factor-κB (NFκB)) or the bone morphogenetic protein (BMP) inhibitor, noggin, led to re-acquisition of NPC properties accompanied by transcriptomic and epigenetic changes consistent with a more neurogenic, NPC-like state. Comparative analyses of microarray data from in vitro-derived and ex vivo postnatal parenchymal astrocytes identified several common pathways and upstream regulators associated with inflammation (including transforming growth factor (TGF)-β1 and peroxisome proliferator-activated receptor gamma (PPARγ)) and cell cycle control (including TP53) as candidate regulators of astrocyte phenotype and potential. We propose that inflammatory signalling may control the normal, progressive restriction in potential of differentiating astrocytes as well as under reactive conditions and represent future targets for therapies to harness the latent neurogenic capacity of parenchymal astrocytes.
KW - Astrocytes
KW - Epigenetic
KW - Inflammation
KW - NFκB
KW - Neural stem cells
KW - Noggin
UR - http://www.scopus.com/inward/record.url?scp=84936802644&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/26138449
U2 - 10.1007/s12035-015-9296-x
DO - 10.1007/s12035-015-9296-x
M3 - Article
C2 - 26138449
AN - SCOPUS:84936802644
SN - 0893-7648
VL - 53
SP - 3724
EP - 3739
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 6
ER -