Abstract
Induced pluripotent stem cells (iPSC) are a most promising approach to the development of a hepatocyte transplantable mass sufficient to induce long-term correction of inherited liver metabolic diseases, thus avoiding liver transplantation. Their intrinsic self-renewal ability and potential to differentiate into any of the three germ layers identify iPSC as the most promising cell-based therapeutics, but also as drivers of tumor development. Teratoma development currently represents the gold standard to assess iPSC pluripotency. We analyzed the tumorigenic potential of iPSC generated from human hepatocytes (HEP-iPSC) and compared their immunohistochemical profiles to that of tumors developed from fibroblast and hematopoietic stem cell-derived iPSC. HEP-iPSC generated tumors significantly presented more malignant morphological features than reprogrammed fibroblasts or CD34+ iPSC. Moreover, the protooncogene myc showed the strongest expression in HEP-iPSC, compared to only faint expression in the other cell subsets. Random integration of transgenes and the use of potent protooncogenes such as myc might be a risk factor for malignant tumor development if hepatocytes are used for reprogramming. Nonviral vector delivery systems or reprogramming of cells obtained from less invasive harvesting methods would represent interesting options for future developments in stem cell-based approaches for liver metabolic diseases.
Highlights
The only treatment for inherited metabolic liver diseases with severe extrahepatic manifestations consists of liver transplantation (LT)
General Pathology Findings. Induced pluripotent stem cells (iPSC) were generated from different human cell sources: hepatocytes, fibroblasts, and hematopoietic stem cells
In an attempt to clarify the confusion in terminology, the position by Nature Biotechnology was to consider “teratocarcinoma” as a malignant tumor composed of both somatic tissues and undifferentiated embryonal carcinoma cells [26]
Summary
The only treatment for inherited metabolic liver diseases with severe extrahepatic manifestations consists of liver transplantation (LT). Gene therapy of diseased hepatocytes followed by their autotransplantation is an alternative approach to LT, as they allow correction of the metabolic defect while avoiding immunosuppression and responding to the shortage of donor livers. The major obstacle for a sufficient, long-term correction of the disease by this method is the insufficient amount of autotransplantable hepatocytes. One strategy for increasing the hepatocyte transplantable mass would be the use of stem cells. Induced pluripotent stem cells (iPSC) are endowed with intrinsic self-renewal ability and the potential to differentiate into any of the three germ layers and can be used to increase the hepatocyte transplantable mass. The same properties that make iPSC the most promising avenue for increasing HEP mass carry a risk of tumorigenicity
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