A Novel Role for the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Delta Isoform in Hepatocellular Proliferation.

The phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform (Pik3cd), usually considered immune-specific, was unexpectedly identified as a gene potentially related to either regeneration and/or differentiation in animals lacking hepatocellular Integrin Linked Kinase (ILK). Since a specific inhibitor (Idelalisib, or CAL101) for the catalytic subunit encoded by Pik3cd (p110δ) has reported hepatotoxicity when used for treating chronic lymphocytic leukemia and other lymphomas, the authors aimed to elucidate whether there is a role for p110δ in normal liver function. To determine the effect on normal liver regeneration, partial hepatectomy (PHx) was performed using mice in which p110δ was first inhibited using CAL101. Inhibition led to over a 50% decrease in proliferating hepatocytes in the first 2 days after PHx. This difference correlated with phosphorylation changes in the HGF and EGF receptors (MET and EGFR, respectively) and NF-κB signaling. Ingenuity Pathway Analyses implicated C/EBPß, HGF, and the EGFR heterodimeric partner, ERBB2, as three of the top 20 regulators downstream of p110δ signaling because their pathways were suppressed in the presence of CAL101 at 1 day post-PHx. A regulatory role for p110δ signaling in mouse and rat hepatocytes through MET and EGFR was further verified using hepatocyte primary cultures, in the presence or absence of CAL101. Combined, these data support a role for p110δ as a downstream regulator of normal hepatocytes when stimulated to proliferate.

Biofabrication of Autologous Human Hepatocytes for Transplantation: How Do We Get There?

Directed differentiation of hepatocytes from induced pluripotent stem cells (iPSCs) holds promise as source material for treating some liver disorders. The unlimited availability of perfectly differentiated iPSC-derived hepatocytes will dramatically facilitate cell therapies. While systems to manufacture large quantities of iPSC-derived cells have been developed, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. This short review highlights important challenges and possible solutions to the current state of hepatocyte biofabrication for cellular therapies to treat liver diseases. Successful cell transplantation will require optimizing the best cell function, overcoming limitations to cell numbers and safety, as well as a number of other challenges. Collaboration among scientists, clinicians, and industry is critical for generating new autologous stem cell-based therapies to treat liver diseases.

Silicon dioxide nanoparticle exposure affects small intestine function in an in vitro model.

The use of nanomaterials to enhance properties of food and improve delivery of orally administered drugs has become common, but the potential health effects of these ingested nanomaterials remain unknown. The goal of this study is to characterize the properties of silicon dioxide (SiO2) nanoparticles (NP) that are commonly used in food and food packaging, and to investigate the effects of physiologically realistic doses of SiO2 NP on gastrointestinal (GI) health and function. In this work, an in vitro model composed of Caco-2 and HT29-MTX co-cultures, which represent absorptive and goblet cells, was used. The model was exposed to well-characterized SiO2 NP for acute (4 h) and chronic (5 d) time periods. SiO2 NP exposure significantly affected iron (Fe), zinc (Zn), glucose, and lipid nutrient absorption. Brush border membrane intestinal alkaline phosphatase (IAP) activity was increased in response to nano-SiO2. The barrier function of the intestinal epithelium, as measured by transepithelial electrical resistance, was significantly decreased in response to chronic exposure. Gene expression and oxidative stress formation analysis showed NP altered the expression levels of nutrient transport proteins, generated reactive oxygen species, and initiated pro-inflammatory signaling. SiO2 NP exposure damaged the brush border membrane by decreasing the number of intestinal microvilli, which decreased the surface area available for nutrient absorption. SiO2 NP exposure at physiologically relevant doses ultimately caused adverse outcomes in an in vitro model.

Titanium Dioxide Nanoparticle Ingestion Alters Nutrient Absorption in an In Vitro Model of the Small Intestine.

Ingestion of titanium dioxide (TiO2) nanoparticles from products such as agricultural chemicals, processed food, and nutritional supplements is nearly unavoidable. The gastrointestinal tract serves as a critical interface between the body and the external environment, and is the site of essential nutrient absorption. The goal of this study was to examine the effects of ingesting the 30 nm TiO2 nanoparticles with an in vitro cell culture model of the small intestinal epithelium, and to determine how acute or chronic exposure to nano-TiO2 influences intestinal barrier function, reactive oxygen species generation, proinflammatory signaling, nutrient absorption (iron, zinc, fatty acids), and brush border membrane enzyme function (intestinal alkaline phosphatase). A Caco-2/HT29-MTX cell culture model was exposed to physiologically relevant doses of TiO2 nanoparticles for acute (four hours) or chronic (five days) time periods. Exposure to TiO2 nanoparticles significantly decreased intestinal barrier function following chronic exposure. Reactive oxygen species (ROS) generation, proinflammatory signaling, and intestinal alkaline phosphatase activity all showed increases in response to nano-TiO2. Iron, zinc, and fatty acid transport were significantly decreased following exposure to TiO2 nanoparticles. This is because nanoparticle exposure induced a decrease in absorptive microvilli in the intestinal epithelial cells. Nutrient transporter protein gene expression was also altered, suggesting that cells are working to regulate the transport mechanisms disturbed by nanoparticle ingestion. Overall, these results show that intestinal epithelial cells are affected at a functional level by physiologically relevant exposure to nanoparticles commonly ingested from food.