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agent with angiogenic, anti-inflammatory and cardioprotective effects on the heart
and which specifically acts on its resident cardiac progenitor cells. Tβ4 is known to
activate the quiescent adult epicardium and specific subsets of epicardial progenitor
cells for repair [ 44 ]. Recently, Tyukavin et al. [ 45 ] reported that the addition of
cardiomyocyte-derived apoptotic bodies to the culture of neonatal myocardial cells
stimulated proliferation and differentiation of cardiomyocyte precursors and the fre-
quency of their contraction was 1.5-fold higher than in the control. Also, systemic
administration of cardiomyocyte-derived apoptotic bodies to Wistar rats with
chronic postinfarction heart failure during the early period of myocardial remodel-
ing considerably improved the contractile function of the heart [ 45 ].
Several studies have tested different strategies to overcome the problem of poor
survival or retention of the cells in the hostile environment of the infracted heart.
Mohsin and colleagues tested the effect of ex vivo gene delivery of a pro-survival
gene, Pim-1 kinase on survival/engraftment and reparative potential of human CSCs
using a mouse model of ischemic cardiomyopathy [ 46 ]. Human CSCs engineered to
overexpress Pim-1 were superior over the control cells in terms of cellular engraft-
ment and differentiation. Also, Pim-1 overexpression does not lead to immortaliza-
tion or oncogenic transformation of CSCs. To enhance retention and engraftment of
CDCs, Cheng et al. [ 47 ] have conducted the intramyocardial injection of CDCs in a
hyaluronan-gelatin hydrogel that improved retention, engraftment and efficacy in
preclinical studies. The CDC-hydrogel combination therapy reduces cell loss due to
leakage by virtue of hydrogel viscosity and by acting as a substrate to which CDCs
can anchor and allows for the gradual migration of CDCs out of the hydrogel and
show prolonged paracrine effects. Pharmacologic activation of innate cytoprotec-
tive mechanisms is also a lucrative option to enhance the in vivo survival and
engraftment of CSCs. Cai et al. have shown that treatment of human c-kit+ CSCs
with cobalt protoporphyrin (CoPP), a well known HO-1 inducer, promoted cell sur-
vival after increased oxidative stress in vitro [ 48 ]. The cytoprotective effects of
CoPP are dependent on the upregulation of HO-1, cyclooxygenase-2, and nuclear
factor-like 2. Interestingly, preconditioning CSCs with CoPP also lead to a global
increase in release of a variety of cytokines, and the conditioned medium from cells
pretreated with CoPP conferred naive CSCs remarkable resistance to apoptosis,
demonstrating that cytokines released by preconditioned cells also play a major role
in the pro-survival effects of CoPP [ 48 ].
7.7 Stimulation of Endogenous CSCs
CSCs produce a repertoire of pro-survival, anti-inflammatory and cardiovascular
regenerative growth factors such as: IGF-1, HGF, TGF-β1 superfamily, including
activins and BMPs, neuregulin-1, periostin, and BMP-10 among others [ 49 ]. It has
been proposed that although the transplanted CSCs themselves survive only tran-
siently and do not directly participate in the production of cells that contributes to
the regenerated tissue, intracoronary injection of allogeneic CSCs in a clinically
S. Kaur et al.