Tissue Engineering: Focus on the Cardiovascular System - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 170

isolated from human BM, and effectively improved heart function upon
transplantation into ischemic myocardium [40]. The possibility of directing
BM cell differentiation toward generation of CM pools, either in vitro or in
vivo, has been intriguing researchers for many years.
Successful in-vitro induction of CMs from BM cell sources [41-47] has
encouraged researchers to assess their therapeutic potential toward repair of
myocardial infarction. Orlic and collaborators were the first to demonstrate
that direct injection of BM stem cells into ischemic cardiac regions can lead
to a rise in CM levels and enhanced heart function [48, 49], a finding subse-
quently substantiated by later works of other groups [50, 51]. In contrast, several
groups have reported limited BM cell plasticity in vivo, suggesting paracrine
activity lacking cell therapeutic value [52-54]. In these studies, BM cells were
reported to differentiate into mature hematopoietic-forming blood cells, but
no CMs were detected in the treated region. Such varied results may be the
result of BM population heterogeny, disparities in cell harvesting techniques
and yields, or the timing of cell injection. However, while the CM-generating
potential of BM cells injected into the infarcted myocardium remains contro-
versial [48, 49, 52-54], the induced improvement in cardiac function remains
unequivocal.
A review of the clinical status of injected BM stem cells uncovers signifi-
cantly discrepant results (see review [55] for a summary table) with regards
to effectiveness of clinically applied BM stem cells [55]. More specifically, the
REPAIR-AMI [56] and BOOST [57] trials reported improved left ventricu-
lar ejection fraction upon BM cells transplantation, where any differences
noted between control and experimental groups became insignificant by the
18-month follow-up examination [58]. Similarly, a meta-analysis summariz-
ing the results of 18 studies, involving a total of 999 patients undergoing
BM cell transplantation in the cardiac tissue [59], concluded that such treat-
ment leads to improved left ventricular ejection fraction, decreased infarct
size, and reduced left ventricular end systolic volume. In contrast, a dou-
bled-blinded, randomized and controlled trial involving transplantations of
similar nature [60] demonstrated a reduction in infarct size, but no change
in left ventricular ejection fraction. These contrasting reports can be rooted
in disparities in cell-harvesting techniques, the timing of cell injection,
administration methods, patient demographics, and the heterogeny of the
BM population used for injection. Despite the inconclusive degree of efficacy
of BM-based transplantation toward renewing cardiac function, all works
demonstrate feasibility, safety, and at least partial efficacy.
Mesenchymal stem cells (MSCs), typically isolated from BM stroma and
capable of differentiating to form osteoblasts, adipocytes, chondrocytes, skel-
etal muscle cells, [61] and others, have recently also been purified from adipose
tissue as well [62]. Their isolation is significantly facilitated by their exten-
sive adhesiveness and lack of hematopoietic markers. Works demonstrating
development of CMs from MSCs stimulated in vitro [45, 63], together with
the less immunogenic nature of MSCs, have initiated transplantation studies