Development of Next-generation Tumor-homing Induced Neural Stem Cells to Enhance Treatment of Metastatic Cancers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE157253 | GEO | 2021/04/16
REPOSITORIES: GEO
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Project description:An organized network of beating cilia transports cerebrospinal fluid (CSF) through the ventricles of the brain. CSF takes along diverse solutes including extracellular vesicles (EV), which arise from the choroid plexus, a secretory epithelium that reaches into the ventricles. Along their path through the ventricles, EVs have the opportunity to contact neural stem cell (NSC) niches. We purified EVZ310 produced by a choroid plexus-cell line, by differential centrifugation and flotation in iodixanol density gradients. We co-cultured suspensions of EVZ310 with NSC from the lateral and third ventricle. Alternatively, EVZ310 were dried-down on a polymer substrate and a suspension of NSCs was added. In both cases, EV Z310 induced, in a dose dependent manner, the NSC to rapidly form cellular networks accompanied by the expression of genes characteristic for neurons (Tuj1) and astrocytes (Gfap). NSCs from either origin responded to EVZ310 qualitatively and quantitatively in a very similar way. By contrast, EVMEF purified from mouse embryonic fibroblasts had little effect on both types of NSC. Mass spectrometry revealed significant differences in composition between EVMEF and EVZ310 proteomes. Notably, EVZ310 were enriched for the membrane or membrane associated proteins known to be involved in neurogenesis, cell differentiation, membrane trafficking and membrane organization.
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Project description:Neural stem cell (NSC) transplantation replaces damaged brain cells and provides disease-modifying effects in many neurological disorders. However, there has been no efficient way to obtain autologous NSCs in patients. Given that ectopic factors can reprogram somatic cells to be pluripotent, we attempted to generate human NSC-like cells by reprograming human fibroblasts. Fibroblasts were transfected with NSC line-derived cellular extracts and grown in neurosphere culture conditions. The cells were then analyzed for NSC characteristics, including neurosphere formation, gene expression patterns, and ability to differentiate. The obtained induced neurosphere-like cells (iNS), which formed daughter neurospheres after serial passaging, expressed neural stem cell markers, and had demethylated SOX2 regulatory regions, all characteristics of human NSCs. The iNS had gene expression patterns that were a combination of the patterns of NSCs and fibroblasts, but they could be differentiated to express neuroglial markers and neuronal sodium channels. These results show for the first time that iNS can be directly generated from human fibroblasts. Further studies on their application in neurological diseases are warranted. We generated induced neural stem cells (iNS) and compared the gene expressions with control cells, which included primary human dermal fibroblast cultured in DMEM media (FB), primary human dermal fibroblast cultured in neurosphere-forming condition (FB_con), and neural stem cell line (F3). The four cell lines (iNS, FB, FB_con, and F3) showed different gene expression patterns. In detail, RNA was isolated using Trizol (Invitrogen) according to the manufacturer's instructions, and was labeled and hybridized to an Affimetrix GeneChip human gene 1.0 ST array (Affimetrix, Santa Clara, CA, USA) as described according to the manufacturer’s instructions. Data were analyzed using Expression Console software version 1.1 (Affimetrix), in which gene expression ratios were normalized by Robust Multichip Analysis according to the manufacturer’s protocol.
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