Biology subjects

Cosacak, M. I.

Publications and source records attributed to Cosacak, M. I..

3 recordsLinked to original sources

bioRxiv2018

Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain

Neural stem cells (NSCs) constitute the reservoir for new cells and might be harnessed for stem cell-based regenerative therapies. Zebrafish has remarkable ability to regenerate its brain by inducing NSC plasticity upon Alzheimers pathology. We recently identified that NSCs enhance their proliferation and neurogenic outcome in an Amyloid-beta42-based (A{beta}42) experimental Alzheimers disease model in zebrafish brain and Interleukin-4 (IL4) is a critical molecule for inducing NSC proliferation in AD conditions. However, the mechanisms by which A{beta}42 and IL4 affect NSCs remained unknown. Using single cell transcriptomics, we determined distinct subtypes of NSCs and neurons in adult zebrafish brain, identified differentially expressed genes after A{beta}42 and IL4 treatments, analyzed the gene ontology and pathways that are affected by A{beta}42 and IL4, and investigated how cell-cell communication is altered through secreted molecules and their receptors. Our results constitute the most extensive resource in the Alzheimers disease model of adult zebrafish brain, are likely to provide unique insights into how A{beta}42/IL4 affects NSC plasticity and yield in novel drug targets for mobilizing neural stem cells for endogenous neuro-regeneration.

neuroscience↗

bioRxiv2017

Instructive starPEG-Heparin biohybrid 3D cultures for modeling human neural stem cell plasticity, neurogenesis, and neurodegeneration

Three-dimensional models of human neural development and neurodegeneration are crucial when exploring stem-cell-based regenerative therapies in a tissue-mimetic manner. However, existing 3D culture systems are not sufficient to model the inherent plasticity of NSCs due to their ill-defined composition and lack of controllability of the physical properties. Adapting a glycosaminoglycan-based, cell-responsive hydrogel platform, we stimulated primary and induced human neural stem cells (NSCs) to manifest neurogenic plasticity and form extensive neuronal networks in vitro. The 3D cultures exhibited neurotransmitter responsiveness, electrophysiological activity, and tissue-specific extracellular matrix (ECM) deposition. By whole transcriptome sequencing, we identified that 3D cultures express mature neuronal markers, and reflect the in vivo make-up of mature cortical neurons compared to 2D cultures. Thus, our data suggest that our established 3D hydrogel culture supports the tissue-mimetic maturation of human neurons. We also exemplarily modeled neurodegenerative conditions by treating the cultures with A{beta}42 peptide and observed the known human pathological effects of Alzheimers disease including reduced NSC proliferation, impaired neuronal network formation, synaptic loss and failure in ECM deposition as well as elevated Tau hyperphosphorylation and formation of neurofibrillary tangles. We determined the changes in transcriptomes of primary and induced NSC-derived neurons after A{beta}42, providing a useful resource for further studies. Thus, our hydrogel-based human cortical 3D cell culture is a powerful platform for studying various aspects of neural development and neurodegeneration, as exemplified for A{beta}42 toxicity and neurogenic stem cell plasticity.\n\nSignificanceNeural stem cells (NSC) are reservoir for new neurons in human brains, yet they fail to form neurons after neurodegeneration. Therefore, understanding the potential use of NSCs for stem cell-based regenerative therapies requires tissue-mimetic humanized experimental systems. We report the adaptation of a 3D bio-instructive hydrogel culture system where human NSCs form neurons that later form networks in a controlled microenvironment. We also modeled neurodegenerative toxicity by using Amyloid-beta4 peptide, a hallmark of Alzheimers disease, observed phenotypes reminiscent of human brains, and determined the global gene expression changes during development and degeneration of neurons. Thus, our reductionist humanized culture model will be an important tool to address NSC plasticity, neurogenicity, and network formation in health and disease.

neuroscience↗

bioRxiv2017

Re-arrangements in the cytoplasmic distribution of small RNAs following the maternal-to-zygotic transition in Drosophila embryos

Small RNAs are known to regulate gene expression during early development. However, the dynamics of interaction between small RNAs and polysomes during this process is largely unknown. 0-1h and 7-8h Drosophila embryos were fractionated on sucrose density gradients into four fractions based on A254 reading (1) translationally inactive messengerribonucleoprotein (mRNP); (2) 60S; (3) monosome; and (4) polysome. Comparative analysis of deep-sequencing reads from fractionated and un-fractionated 0-1h and 8-h embryos revealed development-specific co-sedimentation pattern of small RNAs with the cellular translation machinery. Although most miRNAs did not have a specific preference for any state of the translational machinery, we detected fraction-specific enrichment of some miRNAs such as miR-1-3p, -184-39, 5-5p and 263-5p. More interestingly, we observed dysregulation of a subset of miRNAs in fractionated embryos despite no measurable difference in their amount in unfractionated embryos. Transposon-derived endosiRNAs are over-expressed in 7-8h embryos and are associated mainly with the mRNP fraction. However, transposon-derived piRNAs, which are more abundant in 0-1h embryos, co-sediment primarily with the polysome fractions. These results suggest that there appears to be a complex interplay among the small RNAs with respect to their polysome-cosedimention pattern during early development in Drosophila.

developmental biology↗