We report the presence of pluripotent neural crest stem cells in the adult mammalian hair follicle. Numerous neural crest cells reside in the outer root sheath from the bulge to the matrix at the base of the follicle. Bulge explants from adult mouse whisker follicles yield migratory neural crest cells, which in clonal culture form colonies consisting of over a thousand cells. Clones contain neurons, smooth muscle cells, rare Schwann cells and melanocytes, demonstrating pluripotency of the clone-forming cell. Targeted differentiation into Schwann cells and chondrocytes was achieved with neuregulin-1 and bone morphogenetic protein-2, respectively. Serial cloning in vitro demonstrated self-renewal capability. Together, the data show that the adult mouse whisker follicle contains pluripotent neural crest stem cells, termed epidermal neural crest cells (eNCSC). eNCSC are promising candidates for diverse cell therapy paradigms because of their high degree of inherent plasticity and due to their easy accessibility in the skin.

Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. It is well established that neuronal nitric oxide synthase (nNOS)-derived NO exerts a negative control on the hippocampal neurogenesis. Using genetic and pharmacological methods, we investigated the roles of nNOS in depression induced by chronic mild stress (CMS) in mice. Hippocampal nNOS over-expression was first observed 4 days and remained elevated 21 and 56 days after exposure to CMS. The mice exposed to CMS exhibited behavioral changes typical of depression, and impaired neurogenesis in the hippocampus. The CMS-induced behavioral despair and hippocampal neurogenesis impairment were prevented and reversed in the null mutant mice lacking nNOS gene (nNOS)/)) and in the mice receiving nNOS inhibitor. Disrupting hippocampal neurogenesis blocked the antidepressant effect of nNOS inhibition. Moreover, nNOS)/) mice exhibited antidepressant-like properties. Our findings suggest that nNOS over-expression in the hippocampus is essential for chronic stress-induced depression and inhibiting nNOS signaling in brain may represent a novel approach for the treatment of depressive disorders.

No abstract

Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase Ml (GSTM1), was contrasted with the presence of serum AFB,-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a crosssectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.Primary hepatocellular carcinoma (HCC) is a tumor that occurs at high frequencies in east Asia and subSaharan Africa. In those areas of the world, chronic infection with the hepatitis B-virus (HBV) is the best described risk factor; however, only 20-25% of HBV carriers develop HCC. Exposure to the mycotoxin aflatoxin B1 (AFB1) has also been suggested to increase HCC risk (1), in part because in vitro experiments have demonstrated that AFB1 mutagenic metabolites bind to DNA and are capable of inducing G-to-T transversions (2).In certain areas of the HCC endemic regions, an unusual mutational hot spot has been reported in the p53 tumor suppressor gene (3)(4)(5)(6)(7)(8). This mutation, at the third base of codon 249 in exon 7, is an AGG-to-AGT transversion (arginine to serine). HCCs from other areas of the world have been reported to have markedly lower frequencies of codon 249 mutations (9-16). The geographic distribution of these mutations and the similarity to the transversions produced in vitro by AFB1 suggested to investigators that exposure to AFB1 caused the mutations (3, 4). Recent demonstration of the preferential mutability of codon 249 by rat liver microsome-activated AFB1 in HepG2 cells has supported the hypothesis (17).While rates of chronic HBV infection and AFB1 exposure are both elevated in HCC endemic areas, HCC rates in those regions of Asia are an order of magnitude higher than are the rates in areas of Africa with comparable e...

No abstract