The Use of Induced Pluripotent Stem Cells for the Study and Treatment of Liver Diseases

Abstract

Liver disease is a major global health concern. Liver cirrhosis is one of the leading causes of death in the world and currently the only therapeutic option for end-stage liver disease (e.g., acute liver failure, cirrhosis, chronic hepatitis, cholestatic diseases, metabolic diseases, and malignant neoplasms) is orthotropic liver transplantation. Transplantation of hepatocytes has been proposed and used as an alternative to whole organ transplant to stabilize and prolong the lives of patients in some clinical cases. Although these experimental therapies have demonstrated promising and beneficial results, their routine use remains a challenge due to the shortage of donor livers available for cell isolation, variable quality of those tissues, the potential need for lifelong immunosuppression in the transplant recipient, and high costs. Therefore, new therapeutic strategies and more reliable clinical treatments are urgently needed. Recent and continuous technological advances in the development of stem cells suggest they may be beneficial in this respect. In this review, we summarize the history of stem cell and induced pluripotent stem cell (iPSC) technology in the context of hepatic differentiation and discuss the potential applications the technology may offer for human liver disease modeling and treatment. This includes developing safer drugs and cell-based therapies to improve the outcomes of patients with currently incurable health illnesses. We also review promising advances in other disease areas to highlight how the stem cell technology could be applied to liver diseases in the future. © 2016 by John Wiley & Sons, Inc.

Keywords: cell therapy; cell transplantation; disease-specific induced pluripotent stem cells; human liver disease modeling; liver disease; metabolic liver disease; regenerative medicine.

Figure 14.13.1

Potential use and application of human stem cell technology in bioresearch and medicine. When a sperm fertilizes an egg, a single cell is created; in a few hours, this fertilized egg divides into identical cells, capable of forming an entire organism (totipotent cells). Approximately four days after fertilization, these totipotent cells begin to form the blastocyst, which is a hollow sphere of cells with an inner cell mass. The inner cell mass of the blastocyst can be isolated and cultured to form colonies of cells known as human embryonic stem cells (hESCs). These pluripotent stem cells can form cell types of all three germ layers of the human body (ectoderm, endoderm, and mesoderm) and may undergo further specialization to give rise to more distinctive cells known as multipotent stem cells. Multipotent stem cells are capable of generating some adult cell types but not all cell types of the organism. Adult cells can be reprogrammed in vitro to cells that have cell surface markers, gene expression, and other characteristics of pluripotent stem cells. These adult cells are reprogrammed by introducing a set of key transcription factors into the cells. These cells are known as human induced pluripotent stem cells (hiPSCs) and they are able to form cell types of all three germ layers. Human stem cell technology has the potential to provide unprecedented opportunities to study, treat, and prevent a vast array of human diseases by establishing physiologically relevant cell-based models for biomedical research, regenerative medicine, and personalized drug discovery and testing. Modified from Davila et al., 2009.

Figure 14.13.2

Potential surrogate sources of human hepatocytes from iPSCs for the study and treatment of liver diseases. iPSC-derived hepatocytes from healthy or liver disease patient can be transplanted into chimeric animal models and repopulate the host liver with human cells. Humanized liver animal models provides a biomedical tool not only for drug screening, metabolism and toxicity but also for studying liver pathogenesis of viral etiology, liver regenerations, liver cancer, and in the near future, for cell and gene therapy purposes. Although the potential therapeutic applications of these cells can be foreseen, more preclinical and clinical data (safety, efficacy, mechanisms of action involved in their therapeutic effects) are needed before large scale clinical studies are conducted.

Figure 14.13.3

Potential applications of iPSC technology for the study and treatment of liver diseases. iPSC technology is a remarkable tool for researchers and clinicians to leverage to model liver disease mechanisms and develop suitable strategies for therapy. Briefly, the process starts by performing a biopsy (e.g., liver, skin, etc.) on a disease patient. Cells isolated from the tissue are reprogrammed to establish patient- and disease-specific iPSC lines by forcing expression of specific transcription factors (e.g., OCT3/4, SOX2, cMYC, KLF4, NANOG, LIN28). Genetic mutations can then be corrected by gene targeting approaches (e.g., ZFN, RNA-guided nucleases, etc.) and corrected cells can be differentiated in vitro into viable and functional patient-specific hepatocytes. These corrected hepatocytes can be transplanted back to the disease patient (autologous cell therapy) or to a different patient (allogenic cell therapy). Furthermore, noncorrected disease-specific cells can be differentiated to hepatocytes that recapitulate key disease phenotypes and used for drug development and disease-related research. Specifically, iPSC-derived disease-specific hepatocytes can be used to establish disease models, study pathogenesis of the disease, or to select appropriate and optimal patient-specific drug therapy.