Lineage fate of ductular reactions in liver injury and carcinogenesis.

Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/ß-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.

Increased chromosome 16 disomy rates in human spermatozoa and recurrent spontaneous abortions.

OBJECTIVE: To investigate if unexplained recurrent spontaneous abortions (RSA) are associated with increased rates of aneuploidy in spermatozoa of RSA partners ("RSA-men"). DESIGN: Case-control study. SETTING: Academic research center. PATIENT(S): Patients enrolled at the Hormone and Fertility Center and controls at the Department of Urology (LMU-Munich). INTERVENTION(S): Sperm samples of 11 partners of unexplained RSA cases evaluated for elevated diploidy and disomy levels of chromosomes 1-22, X, and Y by multicolor sperm fluorescence in situ hybridization (FISH). MAIN OUTCOME MEASURE(S): Aneuploidy rates obtained in RSA-men compared with controls from the literature and internally; an increase of the aneuploidy rate was considered statistically significant, when it differed ≥ 2 standard deviations from the mean baseline level in controls. RESULT(S): Our sperm FISH data on RSA men showed increased disomy rates for at least three chromosomes in more than 60% of patients but no statistically significant increase of the overall mean sperm disomy or diploidy rate. In particular, meiotic errors involving chromosome 16 contributed to increased sperm disomy in more than 60% of our patients. CONCLUSION(S): These data suggest that among paternal meiotic errors nondisjunction of chromosome 16 might have similar relative influence on fetal aneuploidy compared with maternal chromosome 16 disomy.