91endoderm differentiation from iPSCs can be promoted by using activin A or a
combination of activin A with hepatocyte growth factor and Wnt3a (Chen et al.
2012 ; Sullivan et al. 2010 ). iPSC-derived hepatocytes were generated by BMP-2/
bFGF and HGF combined with low oxygen culture (Hirschi et al. 2014 ).
Hepatocytes can also be obtained using direct reprogramming. By using Gata4,
Hnf1α, and Foxa3 combined with p19 inactivation, Huang and colleagues success-
fully induced iPSCs into functional hepatocyte-like cells (Huang et al. 2011 ).
Modifi cation strategies have since been introduced using a variety of combinations
of transcription factors (Hnf4α, Foxa1, Foxa2, or Foxa3) (Sekiya and Suzuki 2011 ;
Takayama et al. 2012 ).
Another effi cient differentiation protocol for generating functional hepatocyte-
like cells from iPSCs uses a 3D microscale culture system (Zhang et al. 2014 ). By
this promising approach, a large num ber of hepatocyte-like cells can be generated
from iPSCs; this implies the potential of iPSCs in future industrial and clinical
applications.
4.3.3 Clinical Applications of iPSCs
The fi rst clinical application of iPSCs was reported in Japan in September 2014. A
70-year-old female patient suffering from exudative age-related macular degenera-
tion was transplanted with a cell sheet derived from autologous iPSCs. The primary
aim of this clinical research study was to demonstrate the safety of the transplanta-
tion of the iPSC-derived retinal pigment epithelium (RPE) sheets. Therefore, the
patient would be monitored and evaluated for 1 year.
In this study, autologous iPSCs were produced from skin cells taken from a
patient and then differentiated into RPE cells, and small monolayered sheets were
produced. Before transplantation, RPE sheets went through a rigorous safety and
quality check. Especially, RPE were investigated concerning cell shape and func-
tion and gene expression equivalent to in vivo RPE. The study also confi rmed no
traces of the plasmid used to initially insert genes to reprogram the skin cells and no
undifferentiated cells. iPSC-derived RPE cells also did not show tumorigenicity in
animals.
4.4 Conclusions
iPSCs are a potential therapeutic strategy for disease treatment. After approxi-
mately 10 years of technology development, iPSCs are now ready for clinical appli-
cations. Production of clinical-grade iPSCs has been confi rmed with some
breakthroughs including the complete removal of virus vectors to deliver
4 New Trends in Clinical Applications of Induced Pluripotent Stem Cells