Induced pluripotent stem cell–derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice

Abstract

The ability to generate induced pluripotent stem (iPS) cells from a patient's somatic cells has provided a foundation for organ regeneration without the need for immune suppression. However, it has not been established that the differentiated progeny of iPS cells can effectively reverse failure of a vital organ. Here, we examined whether iPS cell-derived hepatocytes have both the functional and proliferative capabilities needed for liver regeneration in mice with fumarylacetoacetate hydrolase deficiency. To avoid biases resulting from random genomic integration, we used iPS cells generated without viruses. To exclude compensation by hepatocytes not derived from iPS cells, we 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 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.

Reprogrammed Cell?based Therapy for Liver Disease: From Lab to Clinic

“…In vivo studies by Isobe et al (58) showed that liver cells differentiated from iPSCs can save rodent from lethal drug-induced ALF. Indeed, transplanted cells exhibited proliferative and liver functional properties (59).…”

“…Different studies have reported that iPSC-derived hepatocytes promote hepatic regeneration, decrease fibrosis, and stabilize chronic liver disease in mice model (59)(60)(61). Despite these advances, iPSC-derived hepatocytes can temporarily support liver function and are hardly able to regenerate the original structure of the liver and to eliminate collagen deposition (62).…”

New Models for the In Vitro Study of Liver Toxicity: 3D Culture Systems and the Role of Bioreactors

“…Derived from the inner cell mass of preimplantationstage blastocysts  Totipotent stem cells  Self-renewal  Huge proliferative potential  High differentiation potential and plasticity  Expression of early markers of hepatic differentiation  Some mature hepatic functions are maintained  Difficulty to be regulated and maintained under controlled conditions  Risk of oncogenicity  Ethical issues  Limited availability Agarwal et al, 2008Baharvand et al, 2006& 2008Ishii, et al 2010Jozefczuk et al, 2011Liu T et al, 2010Rambhatla , et al, 2003Soto-Gutierrez et al, 2007 Extra-hepatic adult stem cells Bone marrow  Pluripotent stem cells  Inducible to express a number of liver-specific functions  Difficulty to reach full adult hepatocyte phenotype  Less differentiated than primary hepatocytes Avital et al, 2001Chen et al, 2006Chivu et al, 2009Petersen et al, 1999 Adipose tissue  Pluripotent stem cells  Express to some extent specific hepatic functions  Quantitatively less differentiated than HEPG2 cell line  Less differentiated than primary hepatocytes Okura et al, 2010 Umbilical cord blood Takahashi et al, 2007Espejel et al, 2010Hu et al, 2010Q. Feng et al, 2010Sullivan et al, 2010H.…”

Induced Pluripotent Stem Cell Technology and Direct Conversion: New Possibilities to Study and Treat Parkinson’s Disease

“…Mouse as well as human iPSCs have been shown to be capable to differentiate into varying clinically relevant cell types, such as cardiomyocytes [17,18], hepatocytes [19], hematopoetic progenitors [20], oligodendrocytes [21] and specific subtypes of neurons [22,23]. In particular, iPSC-derived DA neurons appear to be a very interesting, clinically relevant cell type (for overview of key studies see Table 1).…”