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We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

Sonodynamic therapy is widely used in clinical studies including cancer therapy. The development of sonosensitizers is important for enhancing the generation of reactive oxygen species (ROS) under sonication. Herein, we have developed poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-modified TiO2 nanoparticles as new biocompatible sonosensitizers with high colloidal stability under physiological conditions. To fabricate biocompatible sonosensitizers, a grafting-to approach was adopted with phosphonic-acid-functionalized PMPC, which was prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) using a newly designed water-soluble RAFT agent possessing a phosphonic acid group. The phosphonic acid group can conjugate with the OH groups on the TiO2 nanoparticles. We have clarified that the phosphonic acid end group is more crucial for creating colloidally stable PMPC-modified TiO2 nanoparticles under physiological conditions than carboxylic-acid-functionalized PMPC-modified ones. Furthermore, the enhanced generation of singlet oxygen (1O2), an ROS, in the presence of PMPC-modified TiO2 nanoparticles was confirmed using a 1O2-reactive fluorescent probe. We believe that the PMPC-modified TiO2 nanoparticles prepared herein have potential utility as novel biocompatible sonosensitizers for cancer therapy. [ABSTRACT FROM AUTHOR]

In this study, we firstly describe the formation of a ternary aggregate of ferrocene (Fc), polyethylene glycol (PEG) and β-cyclodextrin (β-CD). Our results provide strong evidence for the fact that the intermolecular aggregation behaviour leads to a striking change in structure and thermal property of the components aggregated. First of all, several independent experiments give us sufficient information about the structure of the aggregate: (1) the ternary aggregate tends to form a uniform fine-grained sponge structure, generating small particles with higher surface areas; (2) there is a threading mechanism of the PEG chain into the cavities of β-CD, and Fc plays the role of a stabiliser for such an aggregation; (3) there is a continual decrease in electron density of the Fe 2p3/2 region from free Fc to the binary aggregates of Fc and to the ternary aggregate. Next, the ternary aggregate exhibits a one-step degradation mechanism and has much lower thermal stability than free components and especially the physical mixture of the components. We believe that these findings are important and valuable for designing and fabricating polypseudorotaxanes, soft matters and organic/inorganic composite materials. [ABSTRACT FROM PUBLISHER]

The central nervous system (CNS) is increasingly recognized as a critical modulator in the oncogenesis of glioblastoma multiforme (GBM), with interactions between cancer and local neuronal circuits frequently leading to epilepsy; however, the relative contributions of these factors remain unclear. Here, we report a coordinated intratumor shift among distinct cancer subtypes within progenitor-like families of epileptic GBM patients, revealing an accumulation of oligodendrocyte progenitor (OPC)-like subpopulations at the cancer-neuron interface along with heightened electrical signaling activity in the surrounding neuronal networks. The OPC-like cells associated with epilepsy express KCND2, which encodes the voltage-gated K + channel K V 4.2, enhancing neuronal excitability via accumulation of extracellular K + , as demonstrated in patient-derived ex vivo slices, xenografting models, and engineering organoids. Together, we uncovered the essential local circuitry, cellular components, and molecular mechanisms facilitating cancer-neuron interaction at peritumor borders. KCND2 plays a crucial role in mediating nervous system-cancer electrical communication, suggesting potential targets for intervention., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The spinal cord possesses highly complex, finely organized cytoarchitecture guided by two dorsoventral morphogenic organizing centers. Thus, generation of human spinal cord tissue in vitro is challenging. Here, we demonstrated a novel method for generation of human dorsoventral spinal cord organoids using composite scaffolds. Specifically, the spinal cord ventralizing signaling Shh agonist (SAG) was loaded into a porous chitosan microsphere (PCSM), then thermosensitive Matrigel was coated on the surface to form composite microspheres with functional sustained-release SAG, termed as PCSM-Matrigel@SAG. Using PCSM-Matrigel@SAG as the core to induce 3D engineering of human spinal cord organoids from human pluripotent stem cells (ehSC-organoids), we found ehSC-organoids could form dorsoventral spinal cord-like cytoarchitecture with major domain-specific progenitors and neurons. Besides, these ehSC-organoids also showed functional calcium activity. In summary, these ehSC-organoids are of great significance for modeling spinal cord development, drug screening as 3D models for motor neuron diseases, and spinal cord injury repair., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Much investigation is needed to understand the underlying molecular mechanisms of iPSC reprogramming and to improve this technology. Lentivirus-mediated iPSC reprogramming remains the most effective method to study human pluripotency reprogramming. iPSC production is more efficient and consistent in the chemically defined medium. Fibroblasts are the most common starting cells for iPSC generation. Here, we provide a detailed protocol for iPSC generation from human fibroblasts using the GFP-expressing lentiviral vectors in the chemically defined medium.

During development, cortical interneurons (cINs) are generated from the ventral telencephalon, robustly migrate to the dorsal telencephalon, make local synaptic connections, and critically regulate brain circuitry by inhibiting other neurons. Thus, their abnormality is associated with various brain disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited sources with which to study the pathogenesis mechanism of these disorders as well as provide a platform to develop novel therapeutics. By employing spinner culture, we could obtain a >10-fold higher yield of cIN progenitors compared to conventional culture without affecting their phenotype. Generated cIN spheres can be maintained feeder-free up to 10 months and are optimized for passaging and cryopreservation. In addition, we identified a combination of chemicals that synchronously matures generated progenitors into SOX6 + KI67 - migratory cINs and extensively characterized their maturation in terms of metabolism, migration, arborization, and electrophysiology. When transplanted into mouse brains, chemically matured migratory cINs generated grafts that efficiently disperse and integrate into the host circuitry without uncontrolled growth, making them an optimal cell population for cell therapy. Efficient large-scale generation of homogeneous migratory cINs without the need of feeder cells will play a critical role in the full realization of hPSC-derived cINs for development of novel therapeutics.