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Abstract Temozolomide (TMZ) resistance is a major challenge in the treatment of glioblastoma (GBM). Tumour reproductive cells (TRCs) have been implicated in the development of chemotherapy resistance. By culturing DBTRG cells in three-dimensional soft fibrin gels to enrich GBM TRCs and performing RNA-seq analysis, the expression of stanniocalcin-1 (STC), a gene encoding a secreted glycoprotein, was found to be upregulated in TRCs. Meanwhile, the viability of TMZ-treated TRC cells was significantly higher than that of TMZ-treated 2D cells. Analysis of clinical data from CGGA (Chinese Glioma Genome Atlas) database showed that high expression of STC1 was closely associated with poor prognosis, glioma grade and resistance to TMZ treatment, suggesting that STC1 may be involved in TMZ drug resistance. The expression of STC1 in tissues and cells was examined, as well as the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results showed that overexpression of STC1 promoted and knockdown of STC1 inhibited TMZ-induced DNA damage. These results were validated in an intracranial tumour model. These data revealed that STC1 exerts regulatory functions on MGMT expression in GBM, and provides a rationale for targeting STC1 to overcome TMZ resistance.

Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation are limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarction, neuronal death, and glial scarring, and promoted the recovery of motor function. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, which is fast growing and tends to invade surrounding normal brain tissues. Uncovering the molecular and cellular mechanisms of GBM high invasion potential is of great importance for the treatment and prognostic prediction. However, the commonly used two-dimensional (2D) cell culture and analysis system suffers from lack of the heterogeneity and in vivo property of brain tissues. Here, we established a three-dimensional (3D) cell culture-based analysis system that could better recapitulate the heterogeneity of GBM and mimic the in vivo conditions in the brain. The GBM cell lines, DBTRG and U251, were cultured by hanging drop culture into the GBM multicellular spheroids, which were embedded in the optimized 3D brain-stiffness-mimicking matrix gel (0.5 mg/ml Collagen Ⅰ + 3 mg/ml Matrigel+ 3.3 mg/ml Hyaluronic Acid (HA)). The biochemical composition of the optimized matrix gel is similar to that of the brain microenvironment, and the elastic modulus is close to that of the brain tissue. The dynamics of the GBM spheroids was examined using high-content imaging for 60 h, and four metrics including invasion distance, invasion area, single-cell invasion velocity, and directionality were employed to quantify the invasion capacity. The result showed that DBTRG cells possess higher invasion capacity than U251 cells, which was consistent with the results of the classic transwell test. Transcriptome analysis of both cell lines was performed to explore the underlying molecular mechanisms. Our novel brain-stiffness-mimicking matrix gel enables comprehensive invasion analysis of the 3D cultured GBM cells and provides a model basis for in-depth exploration of the mechanisms regulating GBM invasion including the interaction between GBM cells and brain stroma.

Cell death is a common phenomenon in the progression of Alzheimer’s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.