Transdifferentiation is a physiological backup mechanism and alternative to stem‐cell‐mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to replenishing lost cells in preexisting structures, i.e., in the presence of a fully developed scaffold and niche. Here we show that hepatocytes in the adult liver can transdifferentiate to build a structure that failed to form in development––the biliary system in mice that mimic the hepatic phenotype of human Alagille syndrome. The bile ducts forming the new biliary system are fully functional as evidenced by reversal of cholestasis, liver injury and liver fibrosis. Our results reveal the potential of mammalian transdifferentiation and may inform efforts to build organs containing a complex tubular system. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Abstract This article continues the Journal's 2005 series of leaders highlighting areas where laboratory science meets clinical practice. In it Dr Holger Willenbring of the Oregon Stem Cell Center discusses the promise of therapeutic cell fusion and the difficulties that remain in bringing this technique into clinical practice.
Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage-restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of adult Rosa26 reporter mice with an adenoassociated viral vector. We found that newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and that liver progenitor cells contributed minimally to acute hepatocyte regeneration. Further, we found no evidence that biliary injury induced conversion of hepatocytes into biliary epithelial cells. These results therefore restore the previously prevailing paradigms of liver homeostasis and regeneration. In addition, our new vector system will be a valuable tool for timed, efficient, and specific loop out of floxed sequences in hepatocytes.
Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease worldwide.1 Animal models are widely used to investigate the mechanisms of fatty liver disease, but they do not faithfully represent NAFLD in humans.2 Thus, there is strong interest in studying NAFLD pathogenesis directly in humans whenever possible. One strategy that is gaining momentum is to utilize iPSC-derived hepatocytes from individual human subjects in complex cell/organ platforms with the goal of reproducing a NAFLD-like state in vitro.3-6 Our group has taken a different approach, positing that iPSC-Heps from a population of NAFLD patients would provide independent insight into the human disease. In this study we generated iPSCs and iPSC-Heps from a well-defined cohort of NAFLD patients. Our objective was to determine whether as a group, in the absence of any metabolic challenge, they exhibit common disease-specific signatures that are distinct from healthy controls.
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