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Chronic alcohol consumption activates hepatic stellate cells (HSCs) and causes fatty degeneration in the liver. However, the origin of HSCs and the mechanism of fatty changes of the liver have not been fully elucidated. Here, we examined the roles of bone marrow-derived cells (BMDCs) in a mouse model with chronic alcohol consumption. We performed bone marrow transplantation from transgenic mice expressing green fluorescence protein (GFP) to female wild-type and ROSA mice (B6.129S7-Gt 26Sor/J, transgenic mice expressing [beta]-galactosidase, [beta]-gal) and treated them with ethanol (EtOH) for 8 or 16 wk. GFP-expressing BMDCs increased in the liver with EtOH treatment in a time-dependent manner. In response to excess alcohol consumption, [approximately equal to]68% of the BMDCs became activated HSCs in that they expressed [alpha]-smooth muscle actin. Meanwhile, [approximately equal to]67% and [approximately equal to]66% of these BMDCs expressed Tnf-[alpha] and transforming growth factor (Tgf)-[beta]1, respectively, and the activities were further supported by the excessive mRNA expression of Tnf-[alpha] and Tgf-[beta]1 in RT-PCR, respectively. Cell fusion occurs between BMDCs and nonparenchymal cells but scarcely occurs between BMDCs and hepatocytes, demonstrated by double staining of [beta]-gal/GFP and further supported by the Y-chromosome staining. The EtOH withdrawal normalized most of the abnormalities produced by chronic alcohol consumption. These results indicate that excess alcohol consumption stimulates both the homing of HSCs from the bone marrow and their profibrogenic cytokine production in a mouse model of alcohol-induced fatty liver disease. bone marrow transplantation; ethanol; liver fibrosis; hepatic stellate cell

Dorsal root ganglion (DRG) neuron dysfunction occurs in a variety of sensory neuronopathies for which there are currently no satisfactory treatments. Here we describe the development of a strategy to target therapeutic genes to DRG neurons for the treatment of these disorders. We genetically modified an adenovirus (Ad) to generate a helper virus (HV) that was detargeted for native adenoviral tropism and contained DRG homing peptides in the adenoviral capsid fiber protein; we used this HV to generate DRG-targeted helper-dependent Ad (HDAd). In mice, intrathecal injection of this HDAd produced a 100-fold higher transduction of DRG neurons and a markedly attenuated inflammatory response compared with unmodified HDAd. We also injected HDAd encoding the [beta] subunit of [beta]-hexosaminidase (Hexb) into Hexb-deficient mice, a model of the neuronopathy Sandhoff disease. Delivery of the DRG-targeted HDAd reinstated neuron-specific Hexb production, reversed gangliosidosis, and ameliorated peripheral sensory dysfunction. The development of DRG neuron--targeted HDAd with proven efficacy in a preclinical model may have implications for the treatment of sensory neuronopathies of diverse etiologies., Introduction Dysfunction of neurons in dorsal root ganglion (DRG) occurs in a variety of sensory neuronopathies (1), (2), including hereditary (3), autoimmune (4), nutritional (5), metabolic (6), and neoplastic diseases [...]

To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment ( [greater than] 120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, [beta]-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immuno-electron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes., Author(s): Hideto Kojima [1]; Mineko Fujimiya [2]; Kazuhiro Matsumura [1]; Patrick Younan [1]; Hirotsugu Imaeda [2]; Makiko Maeda [1, 2]; Lawrence Chan (corresponding author) [1] Recent studies indicate that optimized [...]