Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Running title: Beneficial and detrimental outcomes of astrogliosis after central nervous system injury. Abbreviations:Ado, adenosine; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate; AP1, activator protein1; AQP, acquaporin; BBB, blood-brain barrier; BDNF, brain-derived growth factor; bFGF, basic fibroblast growth factor; bHLH, basic helix loop helix; BMP, bone morphogenetic protein; CNS, central nervous system; CNTF, ciliary neurotrophic factor;COX-2, cyclooxigenase-2; CREB, cAMP response element binding; CSPGs, chondroitinsulphate proteoglycans; ERK, extracellular signal-regulated kinase; EGF, epidermal growth factor; Eph4A, ephrin 4A; Epo, erythropoietin; ET1, Endothelin 1; ET-R, endothelin receptor; GABA, gamma-aminobutyric acid; GDNF, glial cell-line derived neurotropic factor; GF, growth factor; GFAP, glial fibrillary acidic protein; GLAST, glutamate aspartate transporter; GLT1, glutamate transporter 1; GS, glutamine synthase; IFN , interferon-beta; IFNγ, interferon gamma; IGF1, insulin growth factor1; IL1β, interleukin 1 beta; IL2, interleukin 2; IL6, interleukin 6; IL10, interleukin 10; JAK, Janus protein tyrosine kinases; Lcn2, Lipocalin 2; MAPK, mitogen-activated protein kinase; MMP, matrix metalloprotease; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cell; NFkB, nuclear factor kappa B; NGF, nerve growth factor; NT3, neurotrophin 3; p38MAPK, p38 mitogen-activated protein kinase; PTEN, phosphatase and tensin homolog; SOCS, suppressor of cytokine signaling; SOD, superoxide dismutase; STAT, signal transducers and activators of transcription; TGFα, transforming growth factor alpha;TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor alpha; VCAM1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor. Page 4 of 63A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 4...

Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency

“…The astrocytes used in our study are non-proliferating TD cells, thus reproducing the state of the overwhelming majority of adult brain astrocytes. 25 Deficits in this key feature are the likely reason for a certain degree of DDR activation observed in proliferating astrocytic lines 26,27 and differentiated astrocytes displaying residual proliferation. 28 Importantly, downregulation of DDR is peculiar of astrocytes and is not necessarily associated with terminal differentiation.…”

“…30 In neurons, p53-dependent cell death upon genotoxic stress was also reported, and sometimes associated with their re-entry into cell cycle, 31,32 whereas in vivo astrocytes are only known to re-enter cell cycle under pathological condition of reactive gliosis. 25 In this respect in would be interesting to check whether DDR and apoptosis proficiency of brain astrocytes increase when they undergo injury-induced reactive gliosis. It is therefore possible that different TD cell types are differently radiosensitive, depending on their specific role and physiological context.…”

Stochastic nanoroughness modulates neuron–astrocyte interactions and function via mechanosensing cation channels

“…Dynamic changes to astrocyte-neuron interaction mediated by changes to distal astrocytic processes are known to influence neuron-astrocyte plasticity (15). Although astrocytes are generally stationary cells that provide a supportive network for neuronal cells and synapses, migratory and proliferating astrocytes have been observed in glial scarring, an environment with diminished neuronal function (43,44). In this study, an altered cellular environment in the form of nanotopography was shown to affect astrocyte biophysical attributes (shape and roughness) so as to alter their interaction with neurons.…”

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

“…Cortical brain astrocytes express the full complement of P2Y and P2X receptors, with significant changes in the expression level following traumatic or ischemic events [76]. The purinergic system is directly involved in modulating reactive astrogliosis and astrocyte secretion of cytokines and chemokines in the brain cortex [76].…”