Glia and Neural Stem and Progenitor Cells of the Healthy and Ischemic Brain: The Workplace for the Wnt Signaling Pathway

Knotek, Tomáš; Janečková, Lucie; Kriška, Ján; Kor̆ínek, Vladimír; Andĕrová, Miroslava

doi:10.3390/genes11070804

Cited by 18 publications

(18 citation statements)

References 193 publications

(223 reference statements)

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“…Functional enrichment analysis of the genes that were differentially expressed in samples from mice treated with cisplatin + MRS5980 vs cisplatin alone identified “positive regulation of Wnt signaling pathways” and pathways related to protein synthesis. Wnt signaling has been shown to play an important role in repair especially in the survival of neural stem cells/progenitor cells and regulation of BDNF release, a neurogenic niche which is mandatory for intact cognitive capabilities [ 25 , 41 ]. We and others showed that cisplatin treatment depletes the neurogenic niche [ 9 , 42 ], therefore upregulation of Wnt signaling in response to MRS5980 could be an instrumental signaling pathway to restore cognition.…”

Section: Discussionmentioning

confidence: 99%

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice

Singh

Mahalingam

Squillace

et al. 2022

acta neuropathol commun

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Cisplatin is used to combat solid tumors. However, patients treated with cisplatin often develop cognitive impairments, sensorimotor deficits, and peripheral neuropathy. There is no FDA-approved treatment for these neurotoxicities. We investigated the capacity of a highly selective A3 adenosine receptor (AR) subtype (A3AR) agonist, MRS5980, to prevent and reverse cisplatin-induced neurotoxicities. MRS5980 prevented cisplatin-induced cognitive impairment (decreased executive function and impaired spatial and working memory), sensorimotor deficits, and neuropathic pain (mechanical allodynia and spontaneous pain) in both sexes. At the structural level, MRS5980 prevented the cisplatin-induced reduction in markers of synaptic integrity. In-situ hybridization detected Adora3 mRNA in neurons, microglia, astrocytes and oligodendrocytes. RNAseq analysis identified 164 genes, including genes related to mitochondrial function, of which expression was changed by cisplatin and normalized by MRS5980. Consistently, MRS5980 prevented cisplatin-induced mitochondrial dysfunction and decreased signs of oxidative stress. Transcriptomic analysis showed that the A3AR agonist upregulates genes related to repair pathways including NOTCH1 signaling and chromatin modification in the cortex of cisplatin-treated mice. Importantly, A3AR agonist administration after completion of cisplatin treatment resolved cognitive impairment, neuropathy and sensorimotor deficits. Our results highlight the efficacy of a selective A3AR agonist to prevent and reverse cisplatin-induced neurotoxicities via preventing brain mitochondrial damage and activating repair pathways. An A3AR agonist is already in cancer, clinical trials and our results demonstrate management of neurotoxic side effects of chemotherapy as an additional therapeutic benefit.

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Section: Discussionmentioning

confidence: 99%

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice

Singh

Mahalingam

Squillace

et al. 2022

acta neuropathol commun

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“…The work in our current postnatal studies would suggest that NSCs that endow the postnatal DG develop in an altered trajectory after IUGR. In the mammalian brain, activated NSCs in the DG give rise to proliferating neural progenitor cells, differentiate to DCX + neuroblasts, which gradually mature to terminally differentiated neurons ( Knotek et al, 2020 ). During mid-development of postnatal DG, DCX + neuroblasts have smaller cell volumes with higher mean dendritic lengths in our IUGR offspring.…”

Section: Discussionmentioning

confidence: 99%

Intrauterine Growth Restriction Causes Abnormal Embryonic Dentate Gyrus Neurogenesis in Mouse Offspring That Leads to Adult Learning and Memory Deficits

Brown

Wieben

Murdock

et al. 2021

eNeuro

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Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR offspring of both sexes had short-term adult learning and memory deficits. Prenatally, we found that IUGR caused accelerated embryonic DG neurogenesis and Sox2 + neural stem cell depletion. IUGR mice were marked by decreased hippocampal volumes and decreased doublecortin + neuronal progenitors with increased mean dendritic lengths at postnatal day 18. Consistent with its known molecular role in embryonic DG neurogenesis, we also found evidence for decreased Wnt pathway activity during IUGR. In conclusion, we have discovered that postnatal memory deficits are associated with accelerated NSC differentiation and maturation into glutamatergic granule neurons following IUGR, a phenotype that could be explained by decreased embryonic Wnt signaling.

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“…Similar effects of active Wnt signaling were also observed in our previous study on neonatal NS/PCs ( Kriska et al, 2016 ). Additionally, it has been shown that hypoxia and FCI increase the number of NS/PCs in the hippocampus and SVZ, promote the expansion of neuroblasts 1 month after MCAO, and that canonical Wnt signaling is involved in this process ( Cui et al, 2011 ; Zhang et al, 2014 ; Knotek et al, 2020 ). The importance of Wnt signaling in the differentiation of NS/PCs to neurons under ischemic conditions was also documented by Zhang et al (2016) .…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Promotes Differentiation of Ischemia-Activated Adult Neural Stem/Progenitor Cells to Neuronal Precursors

et al. 2021

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Modulating endogenous regenerative processes may represent a suitable treatment for central nervous system (CNS) injuries, such as stroke or trauma. Neural stem/progenitor cells (NS/PCs), which naturally reside in the subventricular zone (SVZ) of the adult brain, proliferate and differentiate to other cell types, and therefore may compensate the negative consequences of ischemic injury. The fate of NS/PCs in the developing brain is largely influenced by Wingless/Integrated (Wnt) signaling; however, its role in the differentiation of adult NS/PCs under ischemic conditions is still enigmatic. In our previous study, we identified the Wnt/β-catenin signaling pathway as a factor promoting neurogenesis at the expense of gliogenesis in neonatal mice. In this study, we used adult transgenic mice in order to assess the impact of the canonical Wnt pathway modulation (inhibition or hyper-activation) on NS/PCs derived from the SVZ, and combined it with the middle cerebral artery occlusion (MCAO) to disclose the effect of focal cerebral ischemia (FCI). Based on the electrophysiological properties of cultured cells, we first identified three cell types that represented in vitro differentiated NS/PCs – astrocytes, neuron-like cells, and precursor cells. Following FCI, we detected fewer neuron-like cells after Wnt signaling inhibition. Furthermore, the immunohistochemical analysis revealed an overall higher expression of cell-type-specific proteins after FCI, indicating increased proliferation and differentiation rates of NS/PCs in the SVZ. Remarkably, Wnt signaling hyper-activation increased the abundance of proliferating and neuron-like cells, while Wnt pathway inhibition had the opposite effect. Finally, the expression profiling at the single cell level revealed an increased proportion of neural stem cells and neuroblasts after FCI. These observations indicate that Wnt signaling enhances NS/PCs-based regeneration in the adult mouse brain following FCI, and supports neuronal differentiation in the SVZ.

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Glia and Neural Stem and Progenitor Cells of the Healthy and Ischemic Brain: The Workplace for the Wnt Signaling Pathway

Cited by 18 publications

References 193 publications

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice

Intrauterine Growth Restriction Causes Abnormal Embryonic Dentate Gyrus Neurogenesis in Mouse Offspring That Leads to Adult Learning and Memory Deficits

Wnt/β-Catenin Signaling Promotes Differentiation of Ischemia-Activated Adult Neural Stem/Progenitor Cells to Neuronal Precursors

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