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Blood-brain barrier and blood-tumoral barrier formation in glioblastoma: endothelial cells and glioblastoma stem cells at the immune-brain crossroad.
Glioblastoma (GBM) is the most aggressive primary brain tumor characterized by significant cellular and molecular complexity. Central to this complexity are glioma stem cells (GSCs) and the perivascular niche, a specialized microenvironment that integrates signals from the systemic circulation with cues arising from tumor development. Acting as a regulatory hub, the perivascular niche influences GSC proliferation, migration, and resistance to therapy through multiple interactions among vascular, immune, and tumor cell populations. In this review, we focus on GSCs and examine the cellular composition and molecular mechanisms operating within the perivascular niche, highlighting key modes of crosstalk that sustain tumor progression. We furthermore critically evaluate experimental strategies used to study this compartment, including 2D and 3D cell cultures, organoids, and in vivo models, discussing their respective strengths and limitations for testing intercellular interactions and therapeutic approaches. A comprehensive understanding of tumor heterogeneity and the interactions between different tumor cell populations, combined with well-characterized experimental models, is essential for deriving mechanistic insights and informing the development of more effective targeted therapies for GBM, ultimately advancing our knowledge of how tumor-microenvironment interactions drive GBM progression.
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Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems.
Intrinsic apoptosis relies on the ability of the BCL-2 family to induce the formation of pores on the outer mitochondrial membrane. Previous studies have shown that both BAX and BAK are essential during murine embryogenesis, and reports in human cancer cell lines identified non-canonical roles for BAX and BAK in mitochondrial fission during apoptosis. BAX and BAK function in human brain development remains elusive due to the lack of appropriate model systems. Here, we generated BAX/BAK double knockout human-induced pluripotent stem cells (hiPSCs), hiPSC-derived neural progenitor cells (hNPCs), neural rosettes, and cerebral organoids to uncover the effects of BAX and BAK deletion in an in vitro model of early human brain development. We found that BAX and BAK-deficient cells have abnormal mitochondrial morphology and give rise to aberrant cortical structures. We suggest crucial functions for BAX and BAK during human development, including maintenance of homeostatic mitochondrial morphology, which is crucial for proper development of progenitors and neurons of the cortex. Human pluripotent stem cell-derived systems can be useful platforms to reveal novel functions of the apoptotic machinery in neural development.
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Dopamine Neuron Diversity: Recent Advances and Current Challenges in Human Stem Cell Models and Single Cell Sequencing.
Human midbrain dopamine (DA) neurons are a heterogeneous group of cells that share a common neurotransmitter phenotype and are in close anatomical proximity but display different functions, sensitivity to degeneration, and axonal innervation targets. The A9 DA neuron subtype controls motor function and is primarily degenerated in Parkinson's disease (PD), whereas A10 neurons are largely unaffected by the condition, and their dysfunction is associated with neuropsychiatric disorders. Currently, DA neurons can only be reliably classified on the basis of topographical features, including anatomical location in the midbrain and projection targets in the forebrain. No systematic molecular classification at the genome-wide level has been proposed to date. Although many years of scientific efforts in embryonic and adult mouse brain have positioned us to better understand the complexity of DA neuron biology, many biological phenomena specific to humans are not amenable to being reproduced in animal models. The establishment of human cell-based systems combined with advanced computational single-cell transcriptomics holds great promise for decoding the mechanisms underlying maturation and diversification of human DA neurons, and linking their molecular heterogeneity to functions in the midbrain. Human pluripotent stem cells have emerged as a useful tool to recapitulate key molecular features of mature DA neuron subtypes. Here, we review some of the most recent advances and discuss the current challenges in using stem cells, to model human DA biology. We also describe how single cell RNA sequencing may provide key insights into the molecular programs driving DA progenitor specification into mature DA neuron subtypes. Exploiting the state-of-the-art approaches will lead to a better understanding of stem cell-derived DA neurons and their use in disease modeling and regenerative medicine.
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Pharmaceutical strategies utilizing recombinant human serum albumin.
Gene manipulation techniques open up the possibility of making recombinant human serum albumin (rHSA) or mutants with desirable therapeutic properties and for protein fusion products. rHSA can serve as a carrier in synthetic heme protein, thus reversibly carrying oxygen. Myristoylation of insulin results in a prolonged half-life because of self aggregation and increased albumin binding. Preferential albumin uptake by tumor cells serves as the basis for albumin-anticancer drug conjugate formulation. Furthermore, drug targeting can be achieved by incorporating drugs into albumin microspheres whereas liver targeting can be achieved by conjugating drug with galactosylated or mannosylated albumin. Microspheres and nanoparticles of different sizes can, with or without drugs and/or radioisotopes, be used for drug delivery or diagnostic purposes. In vivo implantation of albumin fusion protein expressing cells encapsulated in HSA-alginate coated beads showed promising results compared to organoids in rats. Chimeric peptide strategy with cationized albumin as the transport can deliver drugs via receptor mediated transcytosis through the blood brain barrier. Gene bearing, albumin microbubbles containing ultrasound contrast agents can non-invasively deliver gene after destruction by ultrasound. Various site-directed mutants of HSA can be tailor made depending on the application required.
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Constructing human neural circuits in living systems by transplantation.
Our understanding of how the brain assembles its circuits and how this goes awry in disease remains incomplete. There has been great progress in generating human neurons from stem cells in vitro and, more recently, in constructing circuits with human cells in vivo by transplantation. Here, I highlight approaches, promises, and challenges of growing human neurons in living animals to study human development and disease.
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Genetic and Epigenetic Regulation of Brain Organoids.
Revealing the mechanisms of neural development and the pathogenesis of neural diseases are one of the most challenging missions in life science. Pluripotent stem cells derived brain organoids mimic the development, maturation, signal generation, and function of human brains, providing unique advantage for neurology. Single-cell RNA sequencing (scRNA-Seq) and multielectrode array independently revealed the similarity between brain organoids and immature human brain at early developmental stages, in the context of gene transcription and dynamic network of neuronal signals. Brain organoids provided the unique opportunity to investigate the underlying mechanism of neural differentiation, senescence, and pathogenesis. In this review, we summarized the latest knowledge and technology in the brain organoid field, the current and potential applications in disease models and pre-clinic studies, with emphasizing the importance of transcriptional and epigenetic analysis.
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Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells.
There is significant need to develop physiologically relevant models for investigating human astrocytes in health and disease. Here, we present an approach for generating astrocyte lineage cells in a three-dimensional (3D) cytoarchitecture using human cerebral cortical spheroids (hCSs) derived from pluripotent stem cells. We acutely purified astrocyte-lineage cells from hCSs at varying stages up to 20 months in vitro using immunopanning and cell sorting and performed high-depth bulk and single-cell RNA sequencing to directly compare them to purified primary human brain cells. We found that hCS-derived glia closely resemble primary human fetal astrocytes and that, over time in vitro, they transition from a predominantly fetal to an increasingly mature astrocyte state. Transcriptional changes in astrocytes are accompanied by alterations in phagocytic capacity and effects on neuronal calcium signaling. These findings suggest that hCS-derived astrocytes closely resemble primary human astrocytes and can be used for studying development and modeling disease.
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Insights into 2D and 3D cell culture models for nanoparticle-based drug delivery to glioblastoma.
Glioblastoma (GBM) remains a formidable challenge due to its aggressive nature, protected location within the brain, and resistance to conventional treatments. Its complex tumor microenvironment (TME), coupled with the blood-brain barrier (BBB), hinders drug delivery leading to poor treatment outcomes. Nanoparticles (NPs) offer a promising solution, as they can improve the pharmacokinetic properties of anticancer agents. By functionalizing NPs with targeting molecules, researchers aim to enhance drug concentration in the brain. However, developing effective NP-based therapies requires robust in vitro models that accurately capture the complexities of GBM. Two-dimensional (2D) and three-dimensional (3D) cell culture models provide a versatile platform for studying NP-cell interactions. By customizing cell types, incorporating TME components, and adjusting flow conditions, researchers can tailor these models to specific research questions. While 2D models offer a simpler starting point, 3D models, such as multicellular spheroids and organoids, can more accurately replicate the complex TME, including the BBB and tumor heterogeneity. These models enable a more comprehensive evaluation of NP efficacy and safety, ultimately accelerating drug development and reducing reliance on animal testing.
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Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids.
Suppressed NMDA receptor (NMDAR) function contributes to multiple brain disorders, including schizophrenia, autism spectrum disorder (ASD), and NMDAR encephalitis. Previous attempts to restore NMDAR activity by increasing ambient glycine, a critical co-agonist, through GlyT1 inhibition have yielded mixed outcomes, partly due to GlyT1's extensive expression in essential brainstem regions. Slc6a20a, a glycine transporter widely expressed in cognition-relevant regions such as the cortex and hippocampus, offers a targeted alternative. Here we show that antisense oligonucleotide (ASO)-mediated Slc6a20a inhibition (Slc6a20a-ASO) normalizes ASD-related phenotypes in male Shank2- and Shank3-mutant mice, with model-dependent rescue profiles. Slc6a20a-ASO rescues NMDAR hypofunction and synaptic phospho-proteomic profiles in the prefrontal cortex. Furthermore, ASO targeting human SLC6A20 rescues suppressed NMDAR function in cortical organoids harboring SHANK2 or SHANK3 mutations. These findings underscore the potential and limitations of Slc6a20a/SLC6A20-ASO for treating disorders characterized by NMDAR hypofunction.
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The dynamic nature of genetic risk for schizophrenia within genes regulated by FOXP1 during neurodevelopment.
FOXP1 (Forkhead-box protein P1) is a crucial transcription factor in neural development and is associated with schizophrenia (SCZ). FOXP1-regulated genes may contribute to genetic risk of SCZ and this may vary across different stages of neurodevelopment. We analyzed RNA-seq transcriptomic data from mouse and human models of FOXP1 loss-of-function across prenatal and postnatal developmental stages, including neural stem cells from embryonic mice (E14.5) and human brain organoids (equivalent to second trimester), and cortical tissues from different mouse postnatal stages P0, P7, and P47. P0 in mice corresponds to the third trimester in humans, while P7 and P47 represent early childhood and adolescence, respectively. Linkage disequilibrium score regression assessed if FOXP1-regulated genes were enriched for SCZ heritability. Gene-set enrichment analysis investigated if FOXP1-regulated genes were enriched for SCZ-associated genes reported as differentially expressed in single cortical cell studies. SynGO analysis mapped FOXP1-regulated genes to synaptic locations and functions. FOXP1-regulated genes were enriched for SCZ heritability, with significant results for E14.5, P7 and P47 but not P0. The P7 gene-set showed the strongest enrichment for SCZ-associated genes from single cortical cell studies. FOXP1-regulated genes at both P7 and P47 were involved in multiple synaptic functions and were mainly enriched within glutamatergic excitatory neurons, with P47 also showing enrichment within GABAergic inhibitory neurons. Prenatal FOXP1-regulated genes were enriched in progenitor cells and also mapped to the synapse. Genetic risk for SCZ within FOXP1-regulated genes follows a dynamic trajectory across developmental stages, showing strongest effects at a timepoint that maps to early childhood.