Simona D'APrile

Neural stem cells (NSCs) are multipotent cells of the central nervous system (CNS) capable of self‐renewal, differentiation, and responding to and shaping the surrounding microenvironment. Their continuous crosstalk with surrounding CNS cells is a key component of their therapeutic potential, particularly in tissue repair and regeneration. Communication in the CNS relies on complementary mechanisms, including connexins (Cxs)‐based intercellular communication, to maintain homeostasis and coordinate responses to physiological and pathological stimuli. Itaconate, an endogenous shunt product of the tricarboxylic acid cycle, functions as an immunometabolite involved in inflammation and oxidative stress and has recently been implicated in neuroimmune modulation. Although itaconate influences several signalling cascades and is exchanged between cells and/or released into the extracellular milieu, its effects on Cxs expression in NSCs and whether the modulation of Cxs expression profile represents a driving factor in shaping cell fate remain unclear. Here, we investigated the effect of dimethyl itaconate, a cell‐permeable esterified itaconate derivative, on the expression profile of Cxs in NSCs and its potential to modulate NSCs fate and differentiation. We found that dimethyl itaconate modulates Cxs expression in NSCs, increasing Cx36 levels, and promotes NSCs differentiation toward a neuronal phenotype, while inhibition of Cxs‐based channels with carbenoxolone or mefloquine abolishes these dimethyl itaconate‐induced effects. Collectively, these findings highlight a regulatory role for cell‐permeable itaconate and contribute to the understanding of intercellular communication in the CNS microenvironment, providing insights into potential therapeutic strategies for CNS repair and regeneration.

Connexin 43 (Cx43) is a transmembrane protein involved in the assembly of gap junctions (GJs) and hemichannels (HCs), organized structures that allow the transferring of ions and small signaling molecules between cells and/or extracellular environment, thereby contributing to tissue homeostasis intercellular communication. Cx43 has recently been identified within the mitochondria of cells, suggesting that it may have additional functions beyond its canonical role. Most studies of mitochondrial Cx43 (mt‐Cx43) have been limited to cells of the cardiovascular system, where it appears to play a role in ATP production, calcium homeostasis, and the response to oxidative stress. However, its functions within the central nervous system (CNS) are not fully understood. Recently, it has been observed that Cx43‐forming GJs is one of the key mechanisms that cells use for the transfer of organelles, including mitochondria. Cx43‐mediated mitochondrial transfer is crucial in the CNS, supporting cellular homeostasis and neuroprotection under both physiological and pathological conditions. The dual roles of Cx43 in regulating mitochondrial function and in mediating mitochondrial transfer, raise important questions about how it coordinates these mechanisms. Herein, we reviewed recent findings on the importance of Cx43 and mt‐Cx43 in the healthy and altered CNS environment, with the aim of shedding light on its potential role in CNS homeostasis and as a therapeutic target in neurological disorder in which Cx43 plays a predominant function.

Mesenchymal stem cells have been widely investigated in the field of regenerative medicine and also used as a model to study the differentiation-induction properties of a variety of biomaterials. This study evaluates the osteoinductive potential of novel hydroxyapatite scaffolds functionalized with a phage-displayed peptide (SC1) selected via biopanning for its similarity to bone matrix proteins. The peptide, identified through sequence alignment as a mimotope of osteonectin (SPARC), was used to functionalize scaffolds. Results from SC1 were gathered at different time points (14, 28 and 46 days) and compared with those from nonfunctionalized hydroxyapatite (HA) scaffolds. In vitro experiments, by seeding human adipose-derived stem cells (hASCs), indicated satisfactory biocompatibility for both types of scaffolds. Histochemical observations showed that SC1, better than HA scaffolds, was able to improve hASC osteogenic differentiation, as evaluated through Alizarin Red staining (showing on average a darker staining of 100%). An increase was also observed, especially at early stages (14 days), for osterix (up to 60% increase) and osteonectin immunoexpression (up to 50% increase). In in vivo experiments, cell-free scaffolds of both types were subcutaneously implanted into the backs of mice and analyzed after 2, 4, 8 and 16 weeks. Also, in this case, SC1 more effectively promoted the osteogenic differentiation of infiltrated resident cells. In particular, increased immunoexpression of osterix and osteonectin (+30% and 35%, respectively) was found already at 2 weeks. It can be concluded that SC1 scaffolds may represent a valuable tool to address critical-sized bone defects.

The central nervous system represents a complex environment in which glioblastoma adapts skillfully, unleashing a series of mechanisms suitable for its efficient development and diffusion. In particular, changes in gene expression and mutational events that fall within the domain of epigenetics interact complexly with metabolic reprogramming and stress responses enacted in the tumor microenvironment, which in turn fuel genomic instability by providing substrates for DNA modifications. The aim of this review is to analyze this complex interaction that consolidates several conditions that confer a state of immunosuppression and immunoevasion, making glioblastoma capable of escaping attack and elimination by immune cells and therefore invincible against current therapies. The progressive knowledge of the cellular mechanisms that underlie the resistance of the glioblastoma represents, in fact, the only weapon to unmask its weak points to be exploited to plan successful therapeutic strategies.

Accumulating evidence sustains glial cells as critical players during central nervous system (CNS) development, homeostasis and disease. Olfactory ensheathing cells (OECs), a type of specialized glia cells sharing properties with both Schwann cells and astrocytes, are of critical importance in physiological condition during olfactory system development, supporting its regenerative potential throughout the adult life. These characteristics prompted research in the field of cell-based therapy to test OEC grafts in damaged CNS. Neuroprotective mechanisms exerted by OEC grafts are not limited to axonal regeneration and cell differentiation. Indeed, OEC immunomodulatory properties and their phagocytic potential encourage OEC-based approaches for tissue regeneration in case of CNS injury. Herein we reviewed recent advances on the immune role of OECs, their ability to modulate CNS microenvironment via bystander effects and the potential of OECs as a cell-based strategy for tissue regeneration.

Neurodegenerative disorders are characterized by the progressive loss of central and/or peripheral nervous system neurons. Within this context, neuroinflammation comes up as one of the main factors linked to neurodegeneration progression. In fact, neuroinflammation has been recognized as an outstanding factor for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple sclerosis (MS). Interestingly, neuroinflammatory diseases are characterized by dramatic changes in the epigenetic profile, which might provide novel prognostic and therapeutic factors towards neuroinflammatory treatment. Deep changes in DNA and histone methylation, along with histone acetylation and altered non-coding RNA expression, have been reported at the onset of inflammatory diseases. The aim of this work is to review the current knowledge on this field.

In 2021 the World Health Organization published the fifth and latest version of the Central Nervous System tumors classification, which incorporates and summarizes a long list of updates from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy work. Among the adult-type diffuse gliomas, glioblastoma represents most primary brain tumors in the neuro-oncology practice of adults. Despite massive efforts in the field of neuro-oncology diagnostics to ensure a proper taxonomy, the identification of glioblastoma-tumor subtypes is not accompanied by personalized therapies, and no improvements in terms of overall survival have been achieved so far, confirming the existence of open and unresolved issues. The aim of this review is to illustrate and elucidate the state of art regarding the foremost biological and molecular mechanisms that guide the beginning and the progression of this cancer, showing the salient features of tumor hallmarks in glioblastoma. Pathophysiology processes are discussed on molecular and cellular levels, highlighting the critical overlaps that are involved into the creation of a complex tumor microenvironment. The description of glioblastoma hallmarks shows how tumoral processes can be linked together, finding their involvement within distinct areas that are engaged for cancer-malignancy establishment and maintenance. The evidence presented provides the promising view that glioblastoma represents interconnected hallmarks that may led to a better understanding of tumor pathophysiology, therefore driving the development of new therapeutic strategies and approaches.