SUMMARY
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability and tissue heterogeneity limit their broad applications. Here we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell layer volume resembling microcephaly. Together, our brain region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease, and for compound testing including potential ZIKV antiviral drugs.
SUMMARY
We addressed the precursor role of aging-like spontaneous promoter DNA
hypermethylation in initiating tumorigenesis. Using mouse colon-derived
organoids, we show that promoter hypermethylation spontaneously arises in cells
mimicking the human aging-like phenotype. The silenced genes activate the Wnt
pathway, causing a stem-like state and differentiation defects. These changes
render aged organoids profoundly more sensitive than young ones to
transformation by BrafV600E,
producing the typical human proximal
BRAFV600E-driven colon adenocarcinomas characterized
by extensive, abnormal gene-promoter CpG-island methylation, or the methylator
phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a
panel of the silenced genes markedly sensitizes to
BrafV600E-induced
transformation. Our studies tightly link aging-like epigenetic abnormalities to
intestinal cell fate changes and predisposition to oncogene-driven colon
tumorigenesis.
The technology of organ-on-a-chip tries to mimic the complexity of native tissues in vitro.Important progress has been made recently in using this technology to study the gut with and without microbiota. These in vitro models can serve as an alternative to animal models for studying physiology, pathology, and pharmacology. While these models have greater physiological relevance compared to two-dimensional (2D) cell systems in vitro, endocrine and immunological functions in gut-on-a-chip models are still poorly represented. Furthermore, the construction of complex models, in which different cell types and structures interact, remains a challenge. Generally, gut-on-chip models have the potential to advance our understanding of the basic interactions found within the gut and lay the foundation for future applications in understanding pathophysiology, developing drugs, and personalizing medical treatments.
Thrombosis is a life-threatening pathological condition in which blood clots form in blood vessels, obstructing or interfering with blood flow. Thrombolytic agents (TAs) are enzymes that can catalyze the conversion of plasminogen to plasmin to dissolve blood clots. The plasmin formed by TAs breaks down fibrin clots into soluble fibrin that finally dissolves thrombi. Several TAs have been developed to treat various thromboembolic diseases, such as pulmonary embolisms, acute myocardial infarction, deep vein thrombosis, and extensive coronary emboli. However, systemic TA administration can trigger non-specific activation that can increase the incidence of bleeding. Moreover, protein-based TAs are rapidly inactivated upon injection resulting in the need for large doses. To overcome these limitations, various types of nanocarriers have been introduced that enhance the pharmacokinetic effects by protecting the TA from the biological environment and targeting the release into coagulation. The nanocarriers show increasing half-life, reducing side effects, and improving overall TA efficacy. In this work, the recent advances in various types of TAs and nanocarriers are thoroughly reviewed. Various types of nanocarriers, including lipid-based, polymer-based, and metal-based nanoparticles are described, for the targeted delivery of TAs. This work also provides insights into issues related to the future of TA development and successful clinical translation.
Injectable shear-thinning biomaterials (STBs) have attracted significant attention because of their efficient and localized delivery of cells as well as various molecules ranging from growth factors to drugs. Recently, electrostatic...
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