Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury.

Insulin provides important information to tissues about feeding behavior and energy status. Defective insulin signaling is associated with ageing, tissue dysfunction, and impaired wound healing. In the liver, insulin resistance leads to chronic damage and fibrosis, but it is unclear how tissue-repair mechanisms integrate insulin signals to coordinate an appropriate injury response or how they are affected by insulin resistance. In this study, we demonstrate that insulin resistance impairs local cellular crosstalk between the fibrotic stroma and bipotent adult liver progenitor cells (LPCs), whose paracrine interactions promote epithelial repair and tissue remodeling. Using insulin-resistant mice deficient for insulin receptor substrate 2 (Irs2), we highlight dramatic impairment of proregenerative fibroblast growth factor 7 (Fgf7) signaling between stromal niche cells and LPCs during chronic injury. We provide a detailed account of the role played by IRS2 in promoting Fgf7 ligand and receptor (Fgfr2-IIIb) expression by the two cell compartments, and we describe an insulin/IRS2-dependent feed-forward loop capable of sustaining hepatic re-epithelialization by driving FGFR2-IIIb expression. Finally, we shed light on the regulation of IRS2 and FGF7 within the fibrotic stroma and show-using a human coculture system-that IRS2 silencing shifts the equilibrium away from paracrine epithelial repair in favor of fibrogenesis. Hence, we offer a compelling insight into the contribution of insulin resistance to the pathogenesis of chronic liver disease and propose IRS2 as a positive regulator of communication between cell types and the transition between phases of stromal to epithelial repair.

Nanog regulates primordial germ cell migration through Cxcr4b.

Gonadal development in vertebrates depends on the early determination of primordial germ cells (PGCs) and their correct migration to the sites where the gonads develop. Several genes have been implicated in PGC specification and migration in vertebrates. Additionally, some of the genes associated with pluripotency, such as Oct4 and Nanog, are expressed in PGCs and gonads, suggesting a role for these genes in maintaining pluripotency of the germ lineage, which may be considered the only cell type that perpetually maintains stemness properties. Here, we report that medaka Nanog (Ol-Nanog) is expressed in the developing PGCs. Depletion of Ol-Nanog protein causes aberrant migration of PGCs and inhibits expression of Cxcr4b in PGCs, where it normally serves as the receptor of Sdf1a to guide PGC migration. Moreover, chromatin immunoprecipitation analysis demonstrates that Ol-Nanog protein binds to the promoter region of Cxcr4b, suggesting a direct regulation of Cxcr4b by Ol-Nanog. Simultaneous overexpression of Cxcr4b mRNA and depletion of Ol-Nanog protein in PGCs rescues the migration defective phenotype induced by a loss of Ol-Nanog, whereas overexpression of Sdf1a, the ligand for Cxcr4b, does not restore proper PGC migration. These results indicate that Ol-Nanog mediates PGC migration by regulating Cxcr4b expression.

Wnt signaling has different temporal roles during retinal development.

Differentiation of neural retinal precursor (NRP) cells in vertebrates follows an established order of cell-fate determination associated with exit from the cell cycle. Wnt signaling regulates cell cycle in colon carcinoma cells and has been implicated in different aspects of retinal development in various species. To better understand the biological roles of Wnt in the developing retina, we have used a transgenic and pharmacological approach to manipulate the Wnt signaling pathway during retinal development in medaka embryos. With the use of both approaches, we observed that during the early phase of retinal development Wnt signaling regulated cell cycle progression, proliferation, apoptosis, and differentiation of NRP cells. However, during later phases of retinal development, proliferation and apoptosis were not affected by manipulation of Wnt signaling. Instead, Wnt regulated Vsx1 expression, but not the expression of other retinal cell markers tested. Thus, the response of NRP cells to Wnt signaling is stage-dependent.

Medaka Oct4 is expressed during early embryo development, and in primordial germ cells and adult gonads.

Oct4 is a crucial transcription factor for controlling pluripotency in embryonic stem cells and the epiblast of mouse embryos. We have characterized the expression pattern of medaka (Oryzias latipes) Ol-Oct4 during embryonic development and in the adult gonads. Genomic analysis showed that Ol-Oct4 is the ortholog of zebrafish spg/pou2. However, their expression patterns are not the same, suggesting that Oct4 may play different roles in zebrafish and medaka. Using specific antibodies for the Ol-Oct4 protein, we showed that Ol-Oct4 is also expressed in primordial germ cells, in the spermatogonia (male germ stem cells), and during different stages of oocyte development. These results suggest that Ol-Oct4 plays a post-embryonic role in the maturing gonads and gametes. The Ol-Oct4 mRNA and protein expression patterns are similar to those of mammalian Oct4 and introduce medaka fish as a valid model for the functional and evolutionary study of pluripotency genes in vivo.

Use of Medaka Fish as Vertebrate Model to Study the Effect of Cocoa Polyphenols in the Resistance to Oxidative Stress and Life Span Extension.

Oxidative stress (OS) can induce cell apoptosis and thus plays an important role in aging. Antioxidant foods protect tissues from OS and contribute to a healthier lifestyle. In this study, we described the used of medaka embryos (Oryzias latipes) to study the putative antioxidant capacity of dietary cocoa extract in vertebrates. A polyphenol-enriched cocoa extract regulated the expression of several genes implicated in OS, thereby protecting fish embryos from induced OS. The cocoa extract activated superoxide dismutase enzyme activity in embryos and adult fish tissues, suggesting a common mechanism for protection during embryonic development and adulthood. Furthermore, long-term feeding of the cocoa extract increased fish life span. Our study demonstrates that the polyphenol-enriched cocoa extract decreases OS and extends life span in medaka fish, validating the use of medaka embryos as an economical platform to screen the antioxidant capacity of food compounds.