90
Recently, direct transdifferentiation from somatic cells to cardiomyocytes has
been introduced as a safety protocol with a low risk of tumorigenesis because of
pluripotent stage elimination (Fu et al. 2013 ; Wada et al. 2013 ) (reviewed by
Acimovic et al. 2014 ; Tabar and Studer 2014 ). Many kinds of growth factors and
transcription factors have been discovered to induce direct reprogramming from
somatic cells to cardiomyocytes. Overexpression of trans cription factors including
Gata4, Mef2, and Tbx5 caused the direct transdifferentiation of fi broblasts into car-
diomyocytes (Xu 2012 ). Recently, the role of noncoding microRNAs including
miR-1, miR-133, miR-208, and miR-499 in direct transdifferentiation into cardio-
myocytes has been demonstrated (Piubelli et al. 2014 ; Xin et al. 2013 ; Xu 2012 ).
Although several protocols have been explored, the translational potential of this
approach needs to be determined. Further confi rmation of maturation and function
of transdifferentiation cells is required.
Further application of iPSC-derived cardiomyocytes in regenerative medicine
requires a high-throughput method for cell purifi c ation. Although it is possible to
purify cardiomyocytes from differentiated iPSCs by fl ow cytometry using several
markers such as EMILIN2, SIRPA, and VCAM (reviewed in Sinnecker et al. 2014 ),
specifi c markers for iPSC-derived cardiomyocytes should be explored.
Heart disease is currently considered as the most serious disease with a high
death rate. Some researchers have proposed that cardiomyocyte transplantation may
restore both structure and function of the heart (reviewed by Skalova et al. 2015 ).
Therefore, cardiomyocytes from iPSCs may be a potential source of cells for thera-
peutic intervention in heart regenerative medicine.
4.3.2.3 iPSCs in Diabetic Mellitus and Liver Disease
Owing to the shortage of β-cells for transplantation, iPSCs may be a potential source
of cells to treat diabetic mellitus. I n early studies, a robust protocol to induce human
iPSC differentiation into insulin-producing cells in vitro was published (Kunisada
et al. 2012 ; Zaida et al. 2010 ). Later, Pagliuca and colleagues explored an effi ciency
differentiation protocol using polyhormonal (PH) cells. PH cells resemble fetal
β-cells more than they do mature β-cells, and these cells functioned like primary
β-cells in vitro and in vivo posttransplantation (Pagliuca et al. 2014 ). Another pro-
tocol based on 3D culture combined with forskolin, dexamethasone, Alk5 inhibitor
II, and nicotinamide showed high effi ciency in iPSC differentiation into pancreatic
progenitor cells (Takeuchi et al. 2014 ). A recent study reported the induction of
iPSCs into islet-like clusters via a four-step protocol using biochemical and growth
factors [insulin, transferrin, selenium (ITS), N2, B27, fi broblast growth factor, and
nicotinamide] (Shaer et al. 2015 ). Despite the promising results of the use of iPSCs
in diabetic mellitus, these studies are still in the early stages. Because of the lack of
monitoring of the safety and long-term effi cacy of iPSCs, more research should be
performed.
Many studies have demonstrated that iPSCs can differentiate into hepatocyte-
like cells (Ghodsizadeh 2010 ; Forbes and Newsome 2012 ; Yu et al. 2012 ). Currently,
P.V. Pham et al.