Therapeutic use of R-spondins to augment the cerebrovascular and neuronal Wnt signaling and improve stroke outcome in mice
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ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus
PROVIDER: GSE159455 | GEO | 2023/10/07
REPOSITORIES: GEO
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Project description:Wnt signaling is critical for blood-brain barrier function, neuronal survival and adult neurogenesis, yet Wnt proteins are poorly suited as therapeutics for stroke due to production and pharmacokinetic challenges. Here, we show that R-spondins (RSPOs), a family of easily produced and secreted proteins capable of robustly augmenting Wnt signaling, are widely expressed in adult mouse brain and upregulated upon ischemia and reperfusion injury. Neutralizing endogenous RSPOs with the soluble ectodomains of their membrane receptors LGR5, ZNRF3 and RNF43 increased cerebral infarction in a murine stroke model. Conversely, systemic administration of RSPOs substantially reduced cerebral infarction and improved neurological outcomes. The neuroprotective effects of RSPOs were dependent on LGR4/ZNRF3-mediated augmentation of canonical Wnt/-catenin signaling in endothelial and neuronal cells, which in turn promoted blood-brain barrier integrity, neuronal PDGF-CC expression and survival. Further, RSPOs promotes the proliferation and expansion of neural stem/progenitor cells and post-stroke neurogenesis. Thus, we identify a previously unknown neuroprotective and pro-neurogenic mechanism and describe the therapeutic potential of recombinant RSPOs in ischemic stroke.
2023-10-07 | GSE159454 | GEO
Project description:Although Wnt signaling is critical for blood-brain barrier function, neuronal survival and adult neurogenesis, Wnt proteins are poorly suited as therapeutics for stroke given production and pharmacokinetic challenges. Here, we show that R-spondins (RSPOs), a family of easily produced secreted proteins that robustly augment Wnt signaling, were widely expressed in adult mouse brain and upregulated upon ischemia and reperfusion injury. Neutralizing endogenous RSPOs with their membrane receptor LGR5 and ZNRF3/RNF43 soluble ectodomains increased cerebral infarction in a murine stroke model. Conversely, systemic administration of RSPOs substantially reduced cerebral infarction and improved neurological outcomes. The neuroprotective effects of RSPOs were dependent on LGR4/ZNRF3-mediated canonical Wnt/-catenin signaling in the endothelia, neuronal cells and neural stem/progenitor cells, all of which contributed synergistically to reduce cerebral ischemia/reperfusion injury. Thus, we identified a previously unknown neuroprotective mechanism and the therapeutic potential of recombinant RSPOs in ischemic stroke.
2023-10-07 | GSE159453 | GEO
Project description:Therapeutic use of R-spondins to augment the cerebrovascular and neuronal Wnt signaling and improve stroke outcome in mice
| PRJNA668982 | ENA
Project description:Therapeutic use of R-spondins to augment the cerebrovascular and neuronal Wnt signaling and improve stroke outcome in mice [scRNA-Seq]
| PRJNA668991 | ENA
Project description:Therapeutic use of R-spondins to augment the cerebrovascular and neuronal Wnt signaling and improve stroke outcome in mice [neuron RNA-Seq]
| PRJNA668992 | ENA
Project description:Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and postnatal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists.
| S-EPMC3891875 | biostudies-literature
Project description:As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and (11)C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.
| S-EPMC3887360 | biostudies-other
Project description:Excessive glucose metabolism and disruptions in Wnt signaling are important molecular changes present in oral cancer cells. The aim of this study was to evaluate the effects of the combinatorial use of glycolysis and Wnt signaling inhibitors on viability, cytotoxicity, apoptosis induction, cell cycle distribution and the glycolytic activity of tongue carcinoma cells. CAL 27, SCC-25 and BICR 22 tongue cancer cell lines were used. Cells were treated with inhibitors of glycolysis (2-deoxyglucose and lonidamine) and of Wnt signaling (PRI-724 and IWP-O1). The effects of the compounds on cell viability and cytotoxicity were evaluated with MTS and CellTox Green tests, respectively. Apoptosis was evaluated by MitoPotential Dye staining and cell cycle distribution by staining with propidium iodide, followed by flow cytometric cell analysis. Glucose and lactate concentrations in a culture medium were evaluated luminometrically. Combinations of 2-deoxyglucose and lonidamine with Wnt pathway inhibitors were similarly effective in the impairment of oral cancer cells' survival. However, the inhibition of the canonical Wnt pathway by PRI-724 was more beneficial, based on the glycolytic activity of the cells. The results point to the therapeutic potential of the combination of low concentrations of glycolytic modulators with Wnt pathway inhibitors in oral cancer cells.
| S-EPMC8835497 | biostudies-literature
Project description:A limited amount of functional recovery commonly occurs in the weeks and months after stroke, and a number of studies show that such recovery is associated with changes in the brain's functional organization. Measures that augment this reorganization in a safe and effective way may therefore help improve outcome in stroke patients. Here we review some of the evidence for functional and anatomical reorganization under normal physiological conditions, along with strategies that augment these processes and improve outcome after brain injury in animal models. These strategies include counteracting inhibitors of axon growth associated with myelin, activating neurons' intrinsic growth state, enhancing physiological activity, and having behavioral therapy. These approaches represent a marked departure from the recent focus on neuroprotection and may provide a more effective way to improve outcome after stroke.
| S-EPMC2818530 | biostudies-literature
Project description:The establishment of neuronal polarity is driven by cytoskeletal remodeling that stabilizes and promotes the growth of a single axon from one of the multiple neurites. The importance of the local microtubule stabilization in this process has been revealed however, the external signals initiating the cytoskeletal rearrangements are not completely understood. In this study, we show that local activation of the canonical Wnt pathway regulates neuronal polarity and axonal outgrowth. We found that in the early stages of neuronal polarization, Wnt3a accumulates in one of the neurites of unpolarized cells and thereby could determine axon positioning. Subsequently, Wnt3a localizes to the growing axon, where it activates the canonical Wnt pathway and controls axon positioning and axonal length. We propose a model in which Wnt3a regulates the formation and growth of the axon by activating local intracellular signaling events leading to microtubule remodeling.
| S-EPMC6423405 | biostudies-literature