Imaging in Stem Cell Transplant and Cell-based Therapy

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reproducible, with over 70% of adult atrial biopsies resulting in robustly expanding
cell populations. Following the addition of transforming growth factor beta, almost
all cells have exhibited differentiation into spontaneously beating myocytes with
characteristic cross striations [ 38 ]. Tang et al. [ 39 ] have described a fibroblast-free
conditional CGM medium to expand Sca-1+ cells from small amount of heart tis-
sue. The study showed that Sca-1+ cells keep their capacity for self-renewal and
clonogenic in vitro with fibroblast-free conditional CGM medium, and can differen-
tiate into cardiomyocytes, endothelial cells, and smooth muscle cells after being
transplanted into ischemia-induced heart of mice. Excluding fibroblasts from CSC
culture is essential because fibroblasts maintain high proliferative potential, and will
overgrow CSCs in cardiospheres [ 39 ]. A study by our group has investigated the
effects of different growth factors on CDCs. CSCs appear to respond to epidermal
growth factor (EGF) more efficiently than other widely used growth factors such as
vascular endothelial growth factor, insulin-like growth factor, basic fibroblast
growth factor, hepatocyte growth factor, transforming growth factor, and platelet-
derived growth factor. Pretreatment with EGF enhanced the expression of cardiac
markers cTN1(+) and MHC(+) in CDCs in comparison to untreated controls [ 40 ].
Another study demonstrated that factors such as PDGF-AA present in MSC-CM
improve migration of resident stem cells from human cardiac tissue [ 41 ].
Studies by Kawaguchi et al. [ 42 ] have demonstrated via in vitro co-culture exper-
iments that c-kit+ CSCs with high expression of GATA-4 enhance the survival and
contractility of adult cardiomyocytes through increased IGF-1 levels and induction
of the IGF-1R signalling pathway, modulates the paracrine survival effect of c-kitpos
GATA-4 high CSCs on adult cardiomyocytes in vitro. The study has shown that
CSCs which express high levels of GATA-4 have a pro-survival effect on cardio-
myocytes due to up-regulation of IGF-1 [ 42 ]. c-kit+ CSCs are also known to express
TNFR2 and that binding of TNF to this receptor can result in CSC activation and
cell cycle entry in association with Lin-28 [ 43 ]. The actin monomer binding pep-
tide, Thymosin β4 (Tβ4), has recently been described as a powerful regenerative

Activation of

CSCs

Culturing CSCs with

growth factors, IGF-1, EGF

Culturing CSCs with
Conditioned media

Incubation of CSCs

with cardiomyocyte-derived

apoptotic bodies

Gene transfectionin ex-vivo CSCs

such as Pim- 1

Combining CSCs with

hyaluronan-gelatin hydrogel

Direct injection of growth factors

to enhance endogenous CSCs such HGF, IGF- 1

Direct in vivo injection of

stem cell modulators

such as Isx

Combinatorial therapy of CSCs

With BM-derived MSCs and EPCs

Fig. 7.1 Strategies used for the in vitro and in vivo activation of cardiac stem cells (CSCs)

7 The Emerging Role of Cardiac Stem Cells in Cardiac Regeneration