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[ 54 ]. Based on their utility in animal studies, SMBs have been utilized in several
clinical trials in patients with severe left ventricular dysfunction post-infarction [ 55 ,
56 ]. Follow-up studies have shown a moderate, but significant increase in the
LVEF. Fetal cardiomyocytes have also been used for cardiomyocyte regeneration in
the 1990s [ 57 – 59 ]. These cells significantly improved cardiac functions and angio-
genesis in the injured animals [ 59 ].
Three populations of stem cells in the bone marrow (BM), HSCs, MSCs and
endothelial progenitor cells (EPCs) have been reported to contribute to heart muscle
repair. The ability of transplanted bone marrow (BM)-derived HSCs to regenerate
the infarcted myocardium has been first shown in 2001 [ 60 ]. All functional HSCs
are Lin− and display high levels of Sca1 and c-kit. The study demonstrated that ckit+
HSCs trans-differentiated into mature cardiomyocytes, smooth muscle cells, and
endothelial cells in a murine model of MI and resulted in improvement of LVEF in
the infracted heart [ 60 ]. Although subsequent studies have challenged the transdif-
ferentiation of HSCs into heart muscle cells, the therapeutic efficacy of BM-HSCs
have been proven in many studies [ 61 ]. Apart from c-kit, many other cell surface
markers have also been identified that define populations enriched for freshly iso-
lated human HSCs, including the CD133+ and CD34+ hematopoietic cells. MSCs
represent less than 0.1% of the BM-mononuclear cells and can be identified as a
subset of cells expressing Sca 1. MSCs have been shown to differentiate into cardio-
myocytes as well as vascular endothelial cells in vitro. However, experimental evi-
dence suggests that when transplanted in vivo, MSCs contribute to neo-vascularisation
and cardiomyocyte protection, via the secretion of paracrine factors. A study has
reported that combined transplantation of hCSCs and hMSCs into the infarct border
zones at 14 days after MI in a swine model leads to twofold-greater reduction in scar
size compared with either cell administered alone and also restores diastolic and
systolic function toward normal after MI [ 62 ]. Major advantages of using MSCs are
firstly they can be isolated from a variety of tissues, including bone marrow, adipose
tissue, cord blood, and also can also be substantially expanded in vitro. Secondly,
they lack major histocompatibility complex II and B7 co-stimulatory molecule
expression, which makes them tolerogenic in the host and thus can be given allo-
genically. EPC act as major players in marrow angiogenesis due to their relevant
clonogenic potential. EPC have been identified by cell surface markers including
CD34, CD133 and vegfr2. EPC isolated from peripheral blood and/or BM has
shown incorporation into sites of physiological and pathological neovascularization
in the endothelium after either systemic injection or direct intramyocardial trans-
plantation in animal models of peripheral limb ischemia and myocardial infarction
[ 63 – 65 ]. Ex vivo expanded gene-modified EPC have been reported to enhance EPC
proliferation, adhesion and impaired neovascularization in an animal model of
experimentally induced limb and myocardial ischemia [ 66 , 67 ]. In our studies, we
have demonstrated that EPCs modified with endothelial nitric oxide synthase gene
show enhanced proliferation, migration and neovascularization both in vitro and in
vivo in rabbit model of hind limb ischemia [ 68 , 69 ].
Various clinical trials have been conducted using BM-stem cells including the
BOOST trial, REPAIR-AMI Trial. Results have demonstrated improvement in
S. Kaur et al.