111relevant MI model activates the resident host CSCs resulting in improved myocardial
cell survival, function, remodeling and regeneration. Thus, although the therapeutic
cells are allogeneic, the regenerative response may be completely autologous
because it is carried out by the resident CSCs. Henceforth, besides using expanded
CSCs for cardiac repair, several studies have also attempted to deliver growth fac-
tors to stimulate resident CPCs and promote myocardial regeneration. Intramyo-
cardial delivery of hepatocyte growth factor (HGF) and insulin-like growth factor-1
(IGF-1) have been employed because CSCs express c-Met and IGF-1- receptors and
HGF is a powerful chemoattractant of CSCs while IGF-1 promotes their division
and survival. Results have demonstrated that CSCs locally activated by HGF and
IGF-1 directly in proximity of a healed infarct can salvage nearly 45% of the infarct
by replacing fibrotic tissue with fully functional myocardium. Intracoronary admin-
istration of IGF-1 and HGF has been shown to affect the paracrine effects of endog-
enous CSCs [ 50 ]. A single dose ranging from 0.5 to 2 μg HGF and 2–8 μg IGF-1,
administered just below the site of left anterior descendent occlusion, 30 min after
acute myocardial infarction (AMI) during coronary reperfusion in the pig trigger a
regenerative response from the c-kit+ CSCs, which is potent, self-sustained and able
to produce significant restoration of the damaged myocardium without the need for
cell transplantation [ 50 ]. IGF-1 and HGF have also been reported to induce CSC
migration, proliferation and functional cardiomyogenic and microvasculature dif-
ferentiation. Furthermore, these growth factors, in a dose-dependent manner, have
been shown to improve cardiomyocyte survival, reduce fibrosis and cardiomyocyte
reactive hypertrophy [ 51 ]. Similar positive effects have been obtained when the
HGF-IGF1 combination is administered trans-endocardially in pigs with a chronic
MI using the NOGA system [ 52 ]. Paracrine engineering of explant-derived CSCs to
overexpress IGF-1 has been depicted to substantially improve cardiac stem cell-
mediated repair by enhancing the long-term survival of transplanted cells and sur-
rounding myocardium [ 52 ]. Russell et al. 2015 have shown that 3,5-disubstituted
isoxazoles (Isx), stem cell-modulator small-molecules originally recovered in a P19
embryonal carcinoma cell-based screen, directs muscle transcriptional programs in
vivo in multipotent Notch-activated epicardium-derived CSCs, generating Notch-
activated adult cardiomyocyte-like precursors. The study has documented that Isx,
administered to adult mice as a once daily intra-peritoneal (ip) injection, robustly
activate cardiac gene programs in multipotent CSCs in vivo, a promising start for a
cardio- regenerative small-molecule. The cardiac regenerative effects of Isx in MI
models, however still warrants further investigation [ 53 ].
7.8 Other Stem Cell Sources for Heart Regeneration
Besides cardiac stem cells, various cell types at different developmental stages,
including adult cells, fetal and embryonic cells have been considered for transplan-
tation into the heart. Initial cardiac cell transplantation efforts have been done using
skeletal myoblasts (SMBs), adult stem cells isolated from skeletal muscle biopsies
7 The Emerging Role of Cardiac Stem Cells in Cardiac Regeneration