Myocardial regeneration, tissue engineering and therapy - Artificial Cells, Cell Engineering and Therapy - page 350

further attesting to the lack of regenerative capability of mammalian myo-
cardium. Following myocardial infarction, the necrotic, apoptotic and stunned
(hibernating) myocardium lead to early reduction of ventricular function.
Infiltration of neutrophils and accumulation of macrophages, followed by the
formation of granulation tissue and scar tissue, result in infarct expansion and
ventricular remodeling that progress into ventricular dysfunction and congestive
heart failure. There are 13.2 million Americans suffering coronary heart disease
with 7.2 million heart attacks and 5 million heart failure patients. 8 Cellular
cardiomyoplasty can be an effective treatment for patients with heart attack or
heart failure. 9,10
Observations in humans 11,12 and animals 13,14 have provided some evidence
that myocyte cellular hyperplasia may occur under certain pathophysiologic
conditions. However, recent studies have clearly documented that a rapid switch
of cardiac myocytes from hyperplasia to hypertrophy occurred during early
postnatal development. 6 Cardiomyocyte DNA synthesis in normal and injured
adult mammalian hearts is extremely rare when myocyte nuclei can be reliably
identified. 15,16 Even though spatially and temporally restricted endomitosis
(chromosome replication leading to polyploidy) or karyokinesis (mitosis and
nuclear division leading to multinucleation) can be induced in heart muscle
cells, 17,18 the incomplete disassembly and presence of myofibrils at the equator
region may physically impede the cytokinesis (cell division) process. 19 Adult
mammalian ventricular cardiomyocytes are terminally differentiated cells that
cannot effectively proliferate to regenerate the injured heart.
The possible existence of stem cells or progenitor cells in neonatal rat
myocardium was suggested in 1996. 20 Recently, the presence of stem cells or
progenitor cells in myocardium of adult human 21 and mature animals 22 has been
reported. So far, several distinct types of stem cells or progenitor cells identified
from the adult mammalian ventricular myocardium with regeneration potential
have been documented by different groups. From adult rat heart the Lin ÿ c-kit
cells are self-renewing, clonogenic and multipotent cells that can differentiate
into myocytes, smooth muscle cells and endothelial cells to replace the acutely
ischemic myocardium. 22 These cells can be delivered by intracoronary route and
they home to the myocardial infarction for myocardial regeneration and
functional improvement. 23 Similar cardiac stem cells have also been identified
in human and dogs by the same group for possible treatment of ischemic heart
failure. 24,25
Another progenitor cell isolated from mouse heart 26 expressing Sca-1 can
express cardiac specific genes in vitro after 5-azacytidine treatment. Intravenous
delivery of these cells into mice 6 hours after myocardial infarction, engrafted
cells expressing cardiac markers. Using a Cre/Lox donor/recipient pair, cardiac
Sca-1 + cells homed to the infarct area with about half of the donor-derived cells
fused with host cardiacmyocytes while the other half differentiated into heart
muscle cells without fusion. 26,27

The isl1 + progenitor cells contributed to