Neural Stem Cell Differentiation Through Wnt/β-Catenin Pathway as a Target for Treatment of Ischemic Brain Injury
Aditya Dutta Gupta
Introduction. The treatment of traumatic brain injury through neural stem cell treatment has been heavily limited by the hostility of the transplantation microenvironment. The growth of NSCs is mediated by the three Wnt pathways, of which one is canonical and two are non-canonical.1 The canonical pathway focuses on the stabilization of the β-catenin protein, which is otherwise destabilized by a destruction complex formed by APC, AXIN, GSK3β, and CK1. Stabilization of the β-catenin gene allows downstream upregulation of Wnt signaling gene products that involve axis patterning, cell fate specification, cell proliferation, and cell migration.2There are methods to enhance this canonical pathway, including upregulating glucocerebrosidase, inhibiting miRNA-148b, and hypoxia induction. Methods. For these experiments, NSCs were transplanted into mice that were given a traumatic brain injury, with motor coordination tested using a Rotarod.3 Immunohistochemistry with confocal laser scanning microscopy was used for analysis, as well as transplantation of NSCs. The assessment of Wnt/β-Catenin antagonism was conducted in vivo through protein markers Dkk1 and Wnt1-Ab.3 Results. NSC treatment with glucocerebrosidase reduced cerebral infarct volume in a statistically significant manner. Bcl-2 expression was suppressed in NSC and glucocerebrosidase treated mice and this reduced apoptotic death of cells.4 Mice treated with NSC and glucocerebrosidase also preserved mitochondrial ultrastructure amidst injury. Similar results were obtained upon miRNA-148b inhibition and hypoxia induction.5 Conclusion. It is necessary to properly regulate the hostile microenvironment in ischemic brain injury for efficacious NSC transplantation as a therapy. In order to alleviate the conditions, glucocerebrosidase, miRNA-148b inhibition, and the advantageous pre-existing condition of hypoxia are factors we can utilize to minimize the hostility of the microenvironment.
- Wang, J., Chen, T., Shan, G., et al. miR-148b Regulates Proliferation and Differentiation of Neural Stem Cells via Wnt/β-Catenin Signaling in Rat Ischemic Stroke Model, Frontiers in Cellular Neuroscience, VOLUME 11, 2017, pg. 329
- Qi C, Zhang J, Chen X, et al. Hypoxia stimulates neural stem cell proliferation by increasing HIF‑1α expression and activating Wnt/β-catenin signaling. Cell Mol Biol (Noisy-le-grand). 2017;63(7):12-19. Published 2017 Aug 15. doi:10.14715/cmb/2017.63.7.2
- Francesca, L., Cataldo, T., Peruzzotti-Jametti, L. et al. Neural Stem Cell Grafts Promote Astroglia-Driven Neurorestoration in the Aged Parkinsonian Brain via Wnt/β-Catenin Signaling. STEM CELLS, Stem Cells, Volume 36, Issue 8, ISSN 1066-5099, https://doi.org/10.1002/stem.2827
- Yang, H., Wang, C., Chen, H. et al. Neural Stem Cell-Conditioned Medium Ameliorated Cerebral Ischemia-Reperfusion Injury in Rats, Stem Cells International, Vol. 2018, Article ID 4659159, 7 pages, 2018, https://doi.org/10.1155/2018/4659159
- Ge, H., Zhang, C., Yang, Y. et al. Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/β-Catenin Pathway After Ischemic Stroke, Frontiers in Molecular Neuroscience, VOLUME 13, 2021, pg. 263 https://www.frontiersin.org/article/10.3389/fnmol.2020.596039