89speed of neural induction. However, regardless of the specifi c neural induction
strategy used, the main challenge during the past 10 years has been to determine
how to combine these approaches and optimize the culture conditions with bio-
chemical and biophysical factors to enrich a specifi c neural lineage.
Recently, direct transdifferentiation from somatic cells to multipotent neural
stem cells has been explored. Fibroblasts and other types of cells have been transdif-
ferentiated directly into neural lineages with combinations of transcription factors
(Ambasudhan et al. 2011 ; Caiazzo et al. 2011 ; Son et al. 2011 ; Vierbuchen et al.
2010 ). This approach would also lower the risk of teratoma formation as a strategy
to bypass the pluripotent stage (Ring et al. 2012 ). A single factor, Sox2, has been
used to direct reprogramming of fi broblasts into multipotent neural stem cells (Ring
et al. 2012 ).
4.3.2.2 iPSCs in Cardiac Regenerative Medicine
Mummery and colleagues explored a model of coculture of human ESCs with
visceral- endoderm-like cells (END-2) to promote cardiomyogenesis of human
ESCs (Mummery et al. 2003 ) (reviewed by (Acimovic et al. 2014 ; Sinnecker et al.
2014 ). Cardiac differentiation has been successful using the same protocol with
iPSCs (Freund et al. 2010 ) (reviewed by Acimovic et al. 2014 ; Sinnecker et al.
2014 ). Cardiac differentiation using this protocol has been considered as one of the
fi rst protocols to direct iPSCs into cardiomyocytes.
EB using the hanging drop method is a common method for generating func-
tional cardiomyocytes from iPSCs (Tabar and Studer 2014 ). Compared with ES
cells, the effi ciency of iPS differentiation into cardiomyocytes is lower (Zhang et al.
2009 ; Zwi et al. 2009 ). In this approach, several differentiation factors, such as
activin A, BMP-4, AA/Nodal, Bmp4, Cerberus, and Wnt3a, have shown high effi -
ciency in inducing iPSC differentiation into cardiomyocytes (Skalova et al. 2015 ).
Recently, these growth factors have been combined with small molecules to pro-
mote the differentiation of iPSCs (Skalova et al. 2015 ). A large number of small
molecules have been used to induce iPSC differe ntiation, including 5-azacytidine
(Qian et al. 2012 ) (reviewed by Liu et al. 2013 ), RepSox (Ichida et al. 2009 ), val-
proic acid (Qian et al. 2012 ), KY02112 (Minami et al. 2012 , Bay K8644 (Mehta
et al. 2014 ), and dimethyl sulfoxide (DMSO) (Chetty et al. 2013 ). These small mol-
ecules are involved in specifi c signaling pathways and function as specifi c inhibitors
(pluripotin, RepSox, valproic acid, KY02112), agonists (Bay K 8644), and regula-
tors (DMSO) of the differentiation process.
Moreover, a model of 3D cell culture using biowire technology, collagen wires,
and electrical stimulation has been explored for iPSC differ entiation to cardiomyo-
cytes (Nunes et al. 2013 ) (reviewed by Acimovic et al. 2014 ; Hirschi et al. 2014 ;
Sinnecker et al. 2014 ). Furthermore, a model of coculture with OP9 cells showed
that iPSCs could be differentiated into endothelial cells and hematopoietic progeni-
tor cells (Choi et al. 2009 ).
4 New Trends in Clinical Applications of Induced Pluripotent Stem Cells