We have developed a renewable, scalable and transgene free human blood-brain barrier model, composed of brain endothelial cells (BECs), generated from human amniotic fluid derived induced pluripotent stem cells (AF-iPSC), which can also give rise to syngeneic neural cells of the neurovascular unit. These AF-iPSC-derived BECs (i-BEC) exhibited high transendothelial electrical resistance (up to 1500 Ω cm2) inducible by astrocyte-derived molecular cues and retinoic acid treatment, polarized expression of functional efflux transporters and receptor mediated transcytosis triggered by antibodies against specific receptors. In vitro human BBB models enable pre-clinical screening of central nervous system (CNS)-targeting drugs and are of particular importance for assessing species-specific/selective transport mechanisms. This i-BEC human BBB model discriminates species-selective antibody- mediated transcytosis mechanisms, is predictive of in vivo CNS exposure of rodent cross-reactive antibodies and can be implemented into pre-clinical CNS drug discovery and development processes.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Due to its high incidence rate and often long-term sequelae, TBI contributes significantly to increasing costs of health care expenditures annually. Unfortunately, advances in the field have been stifled by patient and injury heterogeneity that pose a major challenge in TBI prevention, diagnosis, and treatment. In this review, we briefly discuss the causes of TBI, followed by its prevalence, classification, and pathophysiology. The current imaging detection methods and animal models used to study brain injury are examined. We discuss the potential use of molecular markers in detecting and monitoring the progression of TBI, with particular emphasis on microRNAs as a novel class of molecular modulators of injury and its repair in the neural tissue.

The huge worldwide demand for vaccines targeting SARS-CoV-2 has necessitated the continued development of novel improved formulations capable of reducing the burden of the COVID-19 pandemic. Herein, we evaluated novel protein subunit vaccine formulations containing a resistin-trimerized spike antigen, SmT1. When combined with sulfated lactosyl archaeol (SLA) archaeosome adjuvant, formulations induced robust antigen-specific humoral and cellular immune responses in mice. Antibodies had strong neutralizing activity, preventing viral spike binding and viral infection. In addition, the formulations were highly efficacious in a hamster challenge model reducing viral load and body weight loss even after a single vaccination. The antigen-specific antibodies generated by our vaccine formulations had stronger neutralizing activity than human convalescent plasma, neutralizing the spike proteins of the B.1.1.7 and B.1.351 variants of concern. As such, our SmT1 antigen along with SLA archaeosome adjuvant comprise a promising platform for the development of efficacious protein subunit vaccine formulations for SARS-CoV-2.

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Brain injury continues to be one of the leading causes of disability worldwide. Despite decades of research, there is currently no pharmacologically effective treatment for preventing neuronal loss and repairing the brain. As a result, novel therapeutic approaches, such as cell-based therapies, are being actively pursued to repair tissue damage and restore neurological function after injury. In this study, we examined the neuroprotective potential of amniotic fluid (AF) single cell clones, engineered to secrete glial cell derived neurotrophic factor (AF-GDNF), both in vitro and in a surgically induced model of brain injury. Our results show that pre-treatment with GDNF significantly increases cell survival in cultures of AF cells or cortical neurons exposed to hydrogen peroxide. Since improving the efficacy of cell transplantation depends on enhanced graft cell survival, we investigated whether AF-GDNF cells seeded on polyglycolic acid (PGA) scaffolds could enhance graft survival following implantation into the lesion cavity. Encouragingly, the AF-GDNF cells survived longer than control AF cells in serum-free conditions and continued to secrete GDNF both in vitro and following implantation into the injured motor cortex. AF-GDNF implantation in the acute period following injury was sufficient to activate the MAPK/ERK signaling pathway in host neural cells in the peri-lesion area, potentially boosting endogenous neuroprotective pathways. These results were complemented with promising trends in beam walk tasks in AF-GDNF/PGA animals during the 7 day timeframe. Further investigation is required to determine whether significant behavioural improvement can be achieved at a longer timeframe.

Nitric oxide (NO) plays a key role in neurogenesis as a regulator of cell proliferation and differentiation. NO is synthesized from the amino acid L-arginine by nitric oxide synthases (NOS1, NOS2, and NOS3), which are encoded by separate genes and display different tissue distributions. We used an in vitro model of RA-induced neural differentiation of NT2 cells to examine which of the three NO-synthesizing enzymes is involved in this process. The results revealed a transient induction of NOS3 (known as the constitutively expressed endothelial nitric oxide synthase; eNOS) during the time course of the RA treatment. The peak of gene expression and the nuclear presence of NOS3 protein coincided with cell cycle exit of NT2-derived neuronal precursors. The subsequent analysis of cytosine methylation and histone H3 acetylation of the human NOS3 5' regulatory sequences indicated that epigenetic modifications, especially upstream of the proximal promoter (-734 to -989, relative to exon 2 TSS at +1), were also taking place. NOS1 was expressed only in the differentiated neurons (NT2-N), whereas NOS2 was not expressed at all in this cellular model. Thus, a burst of NO production, possibly required to inhibit neural cell proliferation, was generated by the transient expression of NOS3. This pattern of gene expression, in turn, required epigenetic remodeling of its regulatory region.

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