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  • It is interesting to note that in utero lethality

    2018-10-20

    It is interesting to note, that in utero lethality in FAH−/− pigs, which is correctable by NTBC, provides unique opportunities to study regenerative therapies targeted to the fetus (MacKenzie et al., 2002). As liver injury can be initiated by stopping NTBC at any time in development, FAH−/− pigs could be used to test efficacy of gene therapy and in utero cell transplant approaches at any point during gestation, providing a unique disease model that is currently unavailable. Additionally, FAH-deficiency during development may provide a strong selective advantage for the expansion of transplanted human hepatocytes in utero (Fisher et al., 2013), potentially allowing rapid repopulation of the FAH−/− liver with cells (Azuma et al., 2007) that could be used for various cell therapy approaches for myriad liver disorders. A comparable strategy has already been demonstrated in the pig for generating exogenic pancreas in an apancreatic pig by way of Go 6983 complementation (Matsunari et al., 2013). This success of this procedure was based on the vacant pancreatic niche created by expressing a HES1 transgene driven by the PDX1 promoter which resulted in an apancreatic phenotype. To this point, FAH-deficiency in the developing mouse has been already exploited for liver repopulation with FAH-positive cells (Espejel et al., 2010), suggesting FAH-deficiency could provide a unique niche in the developing FAH−/− pig fetus for repopulation with FAH-positive cells. In conclusion, our data show that FAH−/− pigs represent the first genetically modified large model of a metabolic liver disease. FAH−/− pigs off NTBC die of acute liver failure caused by severe hepatocyte dysfunction due to deficiency of the enzyme FAH. FAH−/− pigs closely resemble the human HT1 phenotype, although differences do exist. We anticipate FAH−/− pigs will provide a tremendous resource for preclinical studies aimed at developing regenerative treatments for metabolic liver disease. Additionally, it can be expected that FAH−/− pigs will provide a clinically relevant model for testing efficacy of various cell therapy approaches, including hepatocytes, liver stem cells, pluripotent stem cell-derived hepatocytes, and induced multipotent progenitor cells.
    Acknowledgments We thank Angela Major of the NIDDK-sponsored Digestive Disease Core Laboratory of the Texas Medical Center (DK56338), LouAnn Gross (Mayo Clinic, Rochester) and Jenny Pattengill (Mayo Clinic, Arizona) for histology support. We thank Denise Rokke (Mayo Clinic, Rochester) for elemental analysis. We thank John Bial and Yecuris INC for financial support of early studies involving FAH deficient pigs.
    Introduction The mouse prostate develops from the urogenital sinus (UGS). Before embryonic day 16 (E16), the UGS is comprised of an outer layer of mesenchyme surrounding an inner epithelial layer from which outgrowth occurs to form the prostate ducts (Price, 1963; Wang et al., 2001). At E16.5–17.5 epithelial buds invade the surrounding mesenchyme and begin the process of ductal morphogenesis that generates the complex ductal structure of the adult prostate (Sugimura and Donjacour, 1986; Timms et al., 1994; Hayward et al., 1996). The adult mouse prostate has distinct anterior, dorsal–lateral and ventral lobes; each lobe is divided into proximal, intermediate and distal regions based on their relative location to the urethra (Salm et al., 2005; Cunha et al., 1987). Prostate development is androgen dependent and involves intimate signaling between epithelial and mesenchymal cells. Maintenance of the adult prostate is also androgen-dependent, and the prostate undergoes rapid involution following castration. This involves epithelial apoptosis concentrated in the distal duct segments, loss of androgen-dependent differentiation in the remaining epithelium and remodeling of the periductal stroma (Sugimura and Donjacour, 1986). This process is completely reversed by androgen supplement. The castration–regeneration cycle can repeat for many rounds without observable defects in the regenerated prostate (Sugimura and Donjacour, 1986). This observation suggested the presence of a progenitor cell population in the adult prostate capable of surviving androgen deprivation and sufficient to regenerate the ductal segments of the intact adult prostate.