Stem Cell Technology for Liver Disease

Abstract

The discovery a few years ago that certain cells from mice and humans could be reprogrammed to become inducible pluripotent stem (iPS) cells holds promise for modeling human disease and for cell replacement therapy. In the August 25th, 2010, online edition of the Journal of Clinical Investigation, 2 independent research groups—one led by Ludovic Vallier, at the University of Cambridge, United Kingdom, and the other led by Holger Willenbring, at the University of California in San Francisco—demonstrate that both possibilities may hold true for iPS cell-derived hepatocytes. In the first study, Vallier et al examined the use of human iPS cells for modeling inherited metabolic disorders of the liver. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate a library of patient-specific human iPS cell lines. Each line was differentiated into hepatocytes using what the researchers say they “believe to be a novel 3-step differentiation protocol in chemically defined conditions.” The resulting cells exhibited properties of mature hepatocytes, such as albumin secretion and cytochrome P450 metabolism. Moreover, cells generated from patients with 3 of the inherited metabolic conditions studied in further detail (α1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathologic features of the diseases affecting the patients from which they were derived, such as aggregation of misfolded α1-antitrypsin in the endoplasmic reticulum, deficient low-density lipoprotein receptor–mediated cholesterol uptake, and elevated lipid and glycogen accumulation. The authors say, “These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathologic dysregulation of key processes within adult cells.” See: http://www.jci.org/articles/view/43122?key=834cc7f6d8b865c5ba88. In the second study, Willenbring et al showed that iPS cell-derived hepatocytes have both the functional and proliferative capabilities needed for liver regeneration in mice. The authors generated chimeric mice in which all hepatocytes were iPS cell derived. In vivo analyses showed that iPS cells were intrinsically able to differentiate into fully mature hepatocytes that provided full liver function. The authors report that the iPS cell–derived hepatocytes also replicated the unique proliferative capabilities of normal hepatocytes and were able to regenerate the liver after transplantation and two-thirds partial hepatectomy. “Thus, our results establish the feasibility of using iPS cells generated in a clinically acceptable fashion for rapid and stable liver regeneration.” See: http://www.jci.org/articles/view/43267?key=3a682a87848af072f6bc. In an accompanying commentary, Dr Linda Greenbaum, at Thomas Jefferson University School of Medicine, Philadelphia, describes how these studies have extended our understanding of the potential for iPS cells to be used for cell replacement therapy and modeling human disease. Still, she cautions that “substantial obstacles must be overcome, however, before iPS cells will be ready for in vivo applications. The most pressing goals include the development of efficient and consistent virus-free reprogramming methods and elimination of undifferentiated iPS cells. The potential to apply these technologies in patient-specific manners will no doubt expand the application of personalized medicine to the field of liver diseases in the near future.”