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Terminally differentiated cells are commonly regarded as the most stable cell state in adult organisms, characterized by growth arrest while fulfilling their specialized functions. A better understanding of the mechanisms involved in promoting cell cycle exit will improve the ability to differentiate pluripotent cells into mature tissues for both pharmacological and therapeutic use. Here, it demonstrates that a hyperosmolar environment enforces a protective p53‐independent quiescent state in immature hepatoma cells and in pluripotent stem cell‐derived models of human hepatocytes and endothelial cells. Prolonged culture in hyperosmolar conditions stimulates changes in gene expression promoting functional cell maturation. Interestingly, hyperosmolar conditions do not only trigger growth arrest and cellular maturation but are also necessary to maintain this maturated state, as switching back to plasma osmolarity reverses the changes in expression of maturation and proliferative markers. Transcriptome analysis revealed sequential stages of osmolarity‐regulated growth arrest followed by cell maturation, mediated by activation of NF‐κВ, and repression of WNT signaling, respectively. This study reveals that a modulated increase in osmolarity serves as a biochemical signal to promote long‐term growth arrest and cellular maturation into different lineages, providing a practical method to generate differentiated hiPSCs that resemble their mature counterpart more closely. [ABSTRACT FROM AUTHOR]

Despite 3D bioprinting having emerged as an advanced method for fabricating complex in vitro models, developing suitable bioinks that fulfill the opposing requirements for the biofabrication window still remains challenging. Although naturally derived hydrogels can better mimic the extracellular matrix (ECM) of numerous tissues, their weak mechanical properties usually result in architecturally simple shapes and patchy functions of in vitro models. Here, this limitation is addressed by a peptide-dendrimer-reinforced bioink (HC-PDN) which contained the peptide-dendrimer branched PEG with end-grafted norbornene (PDN) and the cysteamine-modified HA (HC). The extensive introduction of ethylene end-groups facilitates the grafting of sufficient moieties and enhances thiol-ene-induced crosslinking, making HC-PDN exhibits improved mechanical and rheological properties, as well as a significant reduction in reactive oxygen species (ROS) accumulation than that of methacrylated hyaluronic acid (HAMA). In addition, HC-PDN can be applied for the bioprinting of numerous complex structures with superior shape fidelity and soft matrix microenvironment. A heterogeneous and biomimetic hepatic tissue is concretely constructed in this work. The HepG2-C3As, LX-2s, and EA.hy.926s utilized with HC-PDN and assisted GelMA bioinks closely resemble the parenchymal and non-parenchymal counterparts of the native liver. The bioprinted models show the endothelium barrier function, hepatic functions, as well as increased activity of drug-metabolizing enzymes, which are essential functions of liver tissue in vivo. All these properties make HC-PDN a promising bioink to open numerous opportunities for in vitro model biofabrication. In this manuscript, we introduced a peptide dendrimer system, which belongs to the family of hyperbranched 3D nanosized macromolecules that exhibit high molecular structure regularity and various biological advantages. Specifically, norbornene-modified peptide dendrimer was grafted onto PEG, and hyaluronic acid (HA) was selected as a base material for bioink formulation because it is a component of the ECM. Peptide dendrimers confer the following advantages to bioinks: (a) Geometric symmetry can facilitate construction of bioinks with homogeneous networks; (b) abundant surface functional groups allow for abundant crosslinking points; (c) the biological origin can promote biocompatibility. This study shows conceptualization to application of a peptide-dendrimer bioink to extend the Biofabrication Window of natural bioinks and will expand use of 3D bioprinting of in vitro models. [Display omitted] [ABSTRACT FROM AUTHOR]

The drug discovery and development process is still long, costly, and highly risky. The principal attrition factor is undetected toxicity, with hepatic and cardiac toxicities playing a critical role and being the main responsible of safetyrelated drug withdrawals from the market. Multi Organs-on-Chip (MOoC) represent a disruptive solution to study drug-related effects on several organs simultaneously and to efficiently predict drug toxicity in preclinical trials. Specifically focusing on drug safety, different technological features are applied here to develop versatile MOoC platforms encompassing two culture chambers for generating and controlling the type of communication between a metabolically competent liver model and a functional 3D heart model. The administration of the drug Terfenadine, a cardiotoxic compound liver-metabolized into the noncardiotoxic Fexofenadine, proves that liver metabolism and a fine control over drug diffusion are fundamental to elicit a physio-pathological cardiac response. From these results, an optimized LivHeart platform is developed to house a liver model and a cardiac construct that can be mechanically trained to achieve a beating microtissue, whose electrophysiology can be directly recorded in vitro. The platform is proved able to predict off-target cardiotoxicity of Terfenadine after liver metabolism both in terms of cell viability and functionality. [ABSTRACT FROM AUTHOR]

Liver is involved in several vital functions such as metabolism, secretion, and storage as well as detoxification of several drugs and xenobiotics occurs in the liver itself because it is the most vital organ of the body. India is also called as "Botanical Garden Of World". Conventional medicine is now pursuing the use of natural products such as herbs to provide the support that the liver needs on a daily basis. Many Ayurvedic herbs, such as andrographis, have a long history of traditional use in revitalizing the liver and treating liver dysfunction and disease. Medicinal plant contain certain phytochemicals which posses anti-oxidant activity. Development and scientific studies have validated such herbal medicines or combinations confirming the safety and biological efficacy which is helpful in neutralizing the liver disorder. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) bioprinting technology is an effective method for exploring the biological functions of hepatocytes by building biomimetic 3D microenvironments. Various hepatic tissue models have been developed for disease modeling, drug screening, and tissue regeneration using 3D bioprinting technology. Human-induced pluripotent stem cells (hiPSCs) are a promising cell source for the generation of functional hepatocytes for bioprinting. In this study, we introduced hiPSC-derived hepatocytes (hiPSC-Heps) as mature hepatocytes for the bioprinting of a 3D hepatic tissue model. The 3D-printed (3DP) model facilitated the formation of hiPSC-Hep spheroids with higher viability and proliferation than the commonly used non-printed sandwich-cultured model. hiPSC-Heps in the 3DP model exhibited higher mRNA expression of liver-specific functions than those in the two-dimensional-cultured model. Moreover, enhanced secretion of liver function-related proteins, including α-1-antitrypsin, albumin, and blood urea nitrogen, was observed in the 3DP model. For the evaluation of acetaminophen-induced hepatotoxicity, the 3DP model exhibited a favorable drug response with upregulation of the drug metabolism-related gene cytochrome P450-1A2 (CYP1A2). Overall, the bioprinted hepatic tissue model showed great biofunctional and drug-responsive performance, which could be potentially applied in in vitro toxicological studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2022 He, et al.)