), the authors note that in Fig. 1D Right, the x-axis labels were transposed. The corrected figure and its legend appear below. MECs were isolated from BALB/c mice, cultured for 3 days, irradiated, and analyzed for %SP by Hoechst 33342 staining and flow cytometry. Radiation selectively increased the progenitor fraction (%SP) (P ϭ 0.015 for 2 Gy, 0.008 for 4 Gy, and 0.05 for 6 Gy by the two-tailed t test). (B) MCF-7 cells were analyzed for %SP by Hoechst 33342 staining and flow cytometry. Radiation selectively increased the progenitor fraction (%SP) (P ϭ 0.05 for 0 Gy vs. 4 Gy by the two-tailed t test). (C) Cells were analyzed for Sca1 in the SP 24 h after irradiation. Radiation selectively increased the Sca1 ϩ (progenitor) fraction within the SP by killing the more sensitive Sca1 Ϫ (nonprogenitor) cells (P Ͻ 0.05 for Sca1 ϩ to Sca1 Ϫ at 0 Gy vs. 2-8 Gy). The differences in effects of doses of 2 Gy vs. higher doses were not significant. (D) Anesthetized BALB/c mice were immobilized supine, and mammary glands (entire ventral surface) were irradiated. MECs were isolated 48 h after irradiation and analyzed immediately for Sca1 by flow cytometry. Radiation selectively increased the Sca1 ϩ (progenitor) fraction and decreased the Sca1 Ϫ (nonprogenitor)

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ObjectiveNon-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated.MethodsTwo independent studies were performed to examine whether maternal over-nutrition via exposure to high fat diet (HFD) leads to exacerbated hepatic responses to post-natal HFD and methionine choline deficient (MCD) diets in the offspring. Offspring of both control diet- and HFD-fed dams were weaned onto control and HFD, creating four groups.ResultsWhen compared to their control diet-fed littermates, offspring of HF-dams weaned onto HFD gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation. Similarly, this group revealed significantly greater immune response and pro-fibrogenic gene expression via RNA-seq. In parallel, 7–8 week old offspring were challenged with either control or MCD diets for 3 weeks. Responses to MCD diets were also exacerbated due to maternal HFD as seen by gene expression of classical pro-fibrogenic genes. Quantitative genome-scale DNA methylation analysis of over 1 million CpGs showed persistent epigenetic changes in key genes in tissue development and metabolism (Fgf21, Ppargc1β) with maternal HFD and in cell adhesion and communication (VWF, Ephb2) in the combination of maternal HFD and offspring MCD diets. Maternal HFD also influenced gut microbiome profiles in offspring leading to a decrease in α-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum.ConclusionOur findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.

Wnt signaling plays an important role in developmental and stem cell biology. To test the hypothesis that temporary inhibition of Wnt signaling will enhance granulation tissue and promote angiogenesis in tissue repair, we employed a recently characterized small molecule Wnt inhibitor. Pyrvinium is an FDA-approved drug that we identified as a Wnt inhibitor in a chemical screen for small molecules that stabilize β-catenin and inhibit Axin degradation. Our subsequent characterization of pyrvinium has revealed that its critical cellular target in the Wnt pathway is Casein Kinase 1α. Daily administration of pyrvinium directly into polyvinyl alcohol (PVA) sponges implanted subcutaneously in mice generated better organized and vascularized granulation tissue; this compound also increased the proliferative index of the tissue within the sponges. To evaluate its effect in myocardial repair, we induced a myocardial infarction (MI) by coronary artery ligation and administered a single intramyocardial dose of pyrvinium. Mice were evaluated by echocardiography at 7 and 30 days post-MI and treatment; post mortem hearts were evaluated by histology at 30 days. Pyrvinium reduced adverse cardiac remodeling demonstrated by decreased left ventricular internal diameter in diastole (LVIDD) as compared to a control compound. Increased Ki-67+ cells were observed in peri-infarct and distal myocardium of pyrvinium-treated animals. These results need to be further followed-up to determine if therapeutic inhibition of canonical Wnt may avert adverse remodeling after ischemic injury and its impact on myocardial repair and regeneration.

radiation. Expression of active ␤-catenin enhanced selfrenewal preferentially in the Sca1 + cells, whereas suppressing ␤-catenin with a dominant negative, ␤-engrailed, decreased self-renewal of the Sca1 + cells. Understanding the radioresistance of progenitor cells may be an important factor in improving the treatment of cancer. The COMMA-D␤-geo cell line may provide a useful model to study the signaling pathways that control mammary progenitor cell regulation.