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Diabetic retinopathy has a high probability of causing visual impairment or blindness throughout the disease progression and is characterized by the growth of new blood vessels in the retina at an advanced, proliferative stage. Microglia are a resident immune population in the central nervous system, known to play a crucial role in regulating retinal angiogenesis in both physiological and pathological conditions, including diabetic retinopathy. Physiologically, they are located close to blood vessels and are essential for forming new blood vessels (neovascularization). In diabetic retinopathy, microglia become widely activated, showing a distinct polarization phenotype that leads to their accumulation around neovascular tufts. These activated microglia induce pathogenic angiogenesis through the secretion of various angiogenic factors and by regulating the status of endothelial cells. Interestingly, some subtypes of microglia simultaneously promote the regression of neovascularization tufts and normal angiogenesis in neovascularization lesions. Modulating the state of microglial activation to ameliorate neovascularization thus appears as a promising potential therapeutic approach for managing diabetic retinopathy., (© 2024. The Author(s).)

The secreted factor Epidermal growth factor-like protein 7 (EGFL7) is involved in angiogenesis, vasculogenesis, as well as neurogenesis. Importantly, EGFL7 is also implicated in various pathological conditions, including tumor angiogenesis in human cancers. Thus, understanding the mechanisms through which EGFL7 regulates and promotes blood vessel formation is of clear practical importance. One principle means by which EGFL7's function is investigated is via the expression and purification of the recombinant protein. This mini-review describes three methods used to produce recombinant EGFL7 protein. First, a brief overview of EGFL7's genetics, structure, and function is provided. This is followed by an examination of the advantages and disadvantages of three common expression systems used in the production of recombinant EGFL7; (i) Escherichia coli (E . coli) , (ii) human embryonic kidney (HEK) 293 cells or other mammalian cells, and (iii) a baculovirus-based Sf9 insect cell expression system. Based on the available evidence, we conclude that the baculovirus-based Sf9 insect cell expression currently has the advantages of producing active recombinant EGFL7 in the native conformation with the presence of acceptable posttranslational modifications, while providing sufficient yield and stability for experimental purposes., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The localization, expression, and physiological role of regulatory proteins in the neurogenic niches of the brain is fundamental to our understanding of adult neurogenesis. This study explores the expression and role of the E3-ubiquitin ligase, c-Cbl, in neurogenesis within the subventricular zone (SVZ) of mice. In vitro neurosphere assays and in vivo analyses were performed in specific c-Cbl knock-out lines to unravel c-Cbl's role in receptor tyrosine kinase signaling, including the epidermal growth factor receptor (EGFR) pathway. Our findings suggest that c-Cbl is significantly expressed within EGFR-expressing cells, playing a pivotal role in neural stem cell proliferation and differentiation. However, c-Cbl's function extends beyond EGFR signaling, as its loss upon knock-out stimulated progenitor cell proliferation in neurosphere cultures. Yet, this effect was not detected in hippocampal progenitor cells, reflecting the lack of the EGFR in the hippocampus. In vivo , c-Cbl exerted only a minor proneurogenic influence with no measurable impact on the formation of adult-born neurons. In conclusion, c-Cbl regulates neural stem cells in the subventricular zone via the EGFR pathway but, likely, its loss is compensated by other signaling modules in vivo .

Despite improvements in extracranial therapy, survival rate for patients suffering from brain metastases remains very poor. This is coupled with the incidence of brain metastases continuing to rise. In this review, we focus on core contributions of the blood-brain barrier to the origin of brain metastases. We first provide an overview of the structure and function of the blood-brain barrier under physiological conditions. Next, we discuss the emerging idea of a pre-metastatic niche, namely that secreted factors and extracellular vesicles from a primary tumor site are able to travel through the circulation and prime the neurovasculature for metastatic invasion. We then consider the neurotropic mechanisms that circulating tumor cells possess or develop that facilitate disruption of the blood-brain barrier and survival in the brain's parenchyma. Finally, we compare and contrast brain metastases at the blood-brain barrier to the primary brain tumor, glioma, examining the process of vessel co-option that favors the survival and outgrowth of brain malignancies., (© 2023. The Author(s).)

Elongation of the posterior body axis is distinct from that of the anterior trunk and head. Early drivers of posterior elongation are the neural plate/tube and notochord, later followed by the presomitic mesoderm (PSM), together with the neural tube and notochord. In axolotl, posterior neural plate-derived PSM is pushed posteriorly by convergence and extension of the neural plate. The PSM does not go through the blastopore but turns anteriorly to join the gastrulated paraxial mesoderm. To gain a deeper understanding of the process of axial elongation, a detailed characterization of PSM morphogenesis, which precedes somite formation, and of other tissues (such as the epidermis, lateral plate mesoderm and endoderm) is needed. We investigated these issues with specific tissue labelling techniques (DiI injections and GFP + tissue grafting) in combination with optical tissue clearing and 3D reconstructions. We defined a spatiotemporal order of PSM morphogenesis that is characterized by changes in collective cell behaviour. The PSM forms a cohesive tissue strand and largely retains this cohesiveness even after epidermis removal. We show that during embryogenesis, the PSM, as well as the lateral plate and endoderm move anteriorly, while the net movement of the axis is posterior.

Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies., Competing Interests: The authors declare no conflict of interest.

Neural stem cells reside in the subgranular zone, a specialized neurogenic niche of the hippocampus. Throughout adulthood, these cells give rise to neurons in the dentate gyrus, playing an important role in learning and memory. Given that these core cognitive processes are disrupted in numerous disease states, understanding the underlying mechanisms of neural stem cell proliferation in the subgranular zone is of direct practical interest. Here, we report that mature neurons, neural stem cells and neural precursor cells each secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this hippocampal niche. We further demonstrate that EGFL7 knock-out in a Nestin-CreERT2-based mouse model produces a pronounced upregulation of neurogenesis within the subgranular zone. RNA sequencing identified that the increased expression of the cytokine VEGF-D correlates significantly with the ablation of EGFL7. We substantiate this finding with intraventricular infusion of VEGF-D upregulating neurogenesis in vivo and further show that VEGF-D knock-out produces a downregulation of neurogenesis. Finally, behavioral studies in EGFL7 knock-out mice demonstrate greater maintenance of spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation. Taken together, our findings demonstrate that both EGFL7 and VEGF-D affect neurogenesis in the adult hippocampus, with the ablation of EGFL7 upregulating neurogenesis, increasing spatial learning and memory, and correlating with increased VEGF-D expression., (© 2023. The Author(s).)

Glioblastoma multiforme is the most common and devastating form of brain tumor for which only palliative radio- and chemotherapy exists. Although some clinical studies on vaccination approaches have shown promising efficacy due to their potential to generate long-term immune surveillance against cancer cells, the evasion mechanisms preventing therapy response are largely uncharacterized. Here, we studied the response of glioblastoma-propagating cells (GPCs) to clinically relevant doses of γ radiation. GPCs were treated with 2.5 Gy of γ radiation in seven consecutive cellular passages to select for GPCs with increased colony-forming properties and intrinsic or radiation-induced resistance (rsGPCs). Quantitative proteomic analysis of the cellular signaling platforms of the detergent-resistant membranes (lipid rafts) in GPCs vs. rsGPCs revealed a downregulation of the MHC class I antigen-processing and -presentation machinery. Importantly, the radio-selected GPCs showed reduced susceptibility towards cytotoxic CD8+ T-cell-mediated killing. While previous studies suggested that high-dose irradiation results in enhanced antigen presentation, we demonstrated that clinically relevant sub-lethal fractionated irradiation results in reduced expression of components of the MHC class I antigen-processing and -presentation pathway leading to immune escape.

Human sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing the intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 has been reported to be mutated in a variety of cancer types and the expression of SAMHD1 is dysregulated in many cancers. Therefore, SAMHD1 is regarded as a tumor suppressor in certain tumors. Moreover, it has been proposed that SAMHD1 might fulfill the requirements of a driver gene in tumor development or might promote a so-called mutator phenotype. Besides its role as a dNTPase, several novel cellular functions of SAMHD1 have come to light only recently, including a role as negative regulator of innate immune responses and as facilitator of DNA end resection during DNA replication and repair. Therefore, SAMHD1 can be placed at the crossroads of various cellular processes. The present review summarizes the negative role of SAMHD1 in chemotherapy sensitivity, highlights reported SAMHD1 mutations found in various cancer types, and aims to discuss functional consequences as well as underlying mechanisms of SAMHD1 dysregulation potentially involved in cancer development., (© 2021. The Author(s).)