Hepatic differentiation of mouse iPS cells and analysis of liver engraftment potential of multistage iPS progeny
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ORIGINAL PAPER
Hepatic differentiation of mouse iPS cells and analysis of liver engraftment potential of multistage iPS progeny Anangi Balasiddaiah & Daniel Moreno & Laura Guembe & Jesús Prieto & Rafael Aldabe
Received: 22 December 2012 / Accepted: 5 May 2013 # University of Navarra 2013
Abstract Hepatocyte transplantation is considered a promising therapy for patients with liver diseases. Induced pluripotent stem cells (iPSCs) are an unlimited source for the generation of functional hepatocytes. While several protocols that direct the differentiation of iPSCs into hepatocyte-like cells have already been reported, the liver engraftment potential of iPSC progeny obtained at each step of hepatic differentiation has not yet been thoroughly investigated. In this study, we present an efficient strategy to differentiate mouse iPSCs into hepatocyte-like cells and evaluate their liver engraftment potential at different time points of the protocol (5, 10, 15, and 20 days of differentiation). iPSCs were differentiated in the presence of cytokines, growth factors, and small molecules to finally generate hepatocyte-like cells.
These iPSC-derived hepatocyte-like cells exhibited hepatocyte-associated functions, such as albumin secretion and urea synthesis. When we transplanted iPSC progeny into the spleen, we found that 15- and 20-day iPSC progeny engrafted into the livers and further acquired hepatocyte morphology. In contrast, 5- and 10day iPSC progeny were also able to engraft but did not generate hepatocyte-like cells in vivo. Our data may aid in improving current protocols geared towards the use of iPSCs as a new source of liver-targeted cell therapies. Keywords Hepatic differentiation . Hepatocytederived iPSCs . Hepatocyte-like cell transplantation
Introduction Electronic supplementary material The online version of this article (doi:10.1007/s13105-013-0260-9) contains supplementary material, which is available to authorized users. A. Balasiddaiah : D. Moreno : J. Prieto : R. Aldabe (*) Gene Therapy and Hepatology Area, FIMA University of Navarra, Pamplona, Spain e-mail: [email protected] L. Guembe Morphology Lab, Center for Applied Medical Research (CIMA), FIMA University of Navarra, Pamplona, Spain J. Prieto CIBER-EHD, University of Navarra, Pamplona, Spain J. Prieto Liver Unit, University Clinic, University of Navarra, Pamplona, Spain
Hepatocytes play key roles in drug metabolism and represent an important focus of research studies investigating new medicines and fundamental biological mechanisms in metabolic and viral diseases [8]. While the use of cellbased therapies to treat liver diseases is unquestionably justified, progress in the field has been slow because of two reasons: the shortage of liver organs from which hepatocytes can be isolated and the difficulty in maintaining hepatocytes in culture, as they tend to spontaneously dedifferentiate in vitro [6]. Interestingly, several studies have reported that transplanted hepatocytes can integrate into the host liver parenchyma and restore normal hepatic funct
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