Identification of the molecular programs regulated by the regeneration factor Gata3 in neural stem/progenitor cells
Final Report Abstract
The production on new neurons in the adult stages of vertebrates relies on the presence of specialized stem cell niches and on their plasticity. The response of those stem cells to injuries varies significantly. In mammalian brains, new neurons cannot be formed due to unfavorable environment that involves inflammation and scar formation. The effects of injury on stem cells are also negative. Stem cells cannot form neurons and namely lose their plasticity response. Therefore, we hypothesized that the animals that can regenerate their brains after injuries might be using molecular programs that circumvent the impairment of neural stem cell plasticity. One such vertebrate is zebrafish, which can extensively regenerate its brain after various injuries or insults. Therefore, we hypothesized that zebrafish can teach us which molecular programs are required for our mammalian neural stem cells to function better after injuries, and maybe we can use this knowledge for regenerative therapies in humans. From the start of this project, it was a plausible hypothesis that special molecular programs involved in the regenerative response of the zebrafish brain might lie beneath the substantial regenerative capacity thereof, and might explain the disparity in the aptitude to replenish lost neurons between mammals and fish. We previously identified that zebrafish brain uses a specific molecular programs to activate its stem cells after injury, and this program is required for a successful regeneration response. Therefore, in our project, we investigated the changes in the cellular molecular programs and the expression of various genes in zebrafish brains and in mammalian cells (astrocytes from rat brain). We have identified several candidate genes that are regulated in zebrafish brain and in mammalian cells. We also developed new tools such as 3D culture system of human neural stem cells and improved experimental methods of gene expression in human brain cells. Some of our experimental methods needed to be improved and therefore e started out to develop better and more sophisticated genetic tools in zebrafish. Additionally, in order to increase the likelihood of our findings to be applicable to human brains, we optimized the use of human cells with neuronforming potential in cell cultures and our novel 3D culture conditions. We have also adapted the use of induced pluripotent stem cells into our methodological portfolio. One of our publications (Bhattarai et al., 2016, Cell Report) received extensive media attention with various news segments in national TV channels.
Publications
- Instructive starPEG-Heparin biohybrid 3D cultures for modeling human neural stem cell plasticity, neurogenesis, and neurodegeneration
Christos Papadimitriou, Mehmet I Cosacak, Violeta Mashkaryan, Hilal Celikkaya, Laura Bray, Prabesh Bhattarai, Heike Hollak, Xin Chen, Shuijin He, Christopher L Antos, Alvin Thomas, Jens Friedrichs, Andreas Dahl, Yixin Zhang, Uwe Freudenberg, Carsten Werner, Caghan Kizil
(See online at https://doi.org/10.1101/225243) - Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-β42 toxicity
Christos Papadimitriou, Hilal Celikkaya, Mehmet Ilyas I Cosacak, Violeta Mashkaryan, Prabesh Bhattarai, Weilin Lin, Alvin Thomas, Yixin Zhang, Uwe Freudenberg, Carsten Werner, Caghan Kizil
(See online at https://doi.org/10.1101/227306) - (2016) IL4/STAT6 activates neural stem cells in response to Amyloid-β42 aggregation in adult zebrafish brain. Cell Reports, 17(4): 941-948
Bhattarai P, Thomas AK, Cosacak MI, Papadimitriou C, Mashkaryan V, Froc C, Reinhardt S, Kurth T, Dahl A, Zhang Y, Kizil C
(See online at https://doi.org/10.1016/j.celrep.2016.09.075) - (2017) Modeling Amyloid-beta42 toxicity and neurodegeneration in adult zebrafish brain. JoVE. 128
Bhattarai P, Thomas AK, Mashkaryan V, Cosacak MI, Papadimitriou C, Zhang Y, Kizil C
(See online at https://doi.org/10.3791/56014) - (2017). Human TAUP301L overexpression results in TAU hyperphosphorylation without neurofibrillary tangles in adult zebrafish brain. Scientific Reports. 7(1), 12959
Cosacak MI, Bhattarai P, Bocova L, Dzewas T, Mashkaryan V, Papadimitriou C, Brandt K, Hollak H, Antos CL, Kizil C
(See online at https://doi.org/10.1038/s41598-017-13311-5)
