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According to one set of these studies, new cardiomyocytes are generated by
endogenous CSCs only during myocardial injury and not during normal physiological
wear and tear of heart cells. In this regard, Hsieh et al. [ 20 ] used an elegant inducible
cardiomyocyte-specific transgenic mouse fate-mapping approach to determine the
frequency with which cardiomyocytes are refreshed from stem or precursor cells.
They used a genetic fate mapping system comprised of a transgene encoding a con-
ditional, tamoxifen-dependent Cre recombinase under the regulation of the cardio-
myocyte-restricted myosin heavy chain promoter in conjunction with a
ubiquitously-expressed reporter transgene. Transient exposure to tamoxifen resulted
in the generation of adult mice which expressed green fluorescent protein (GFP) in
terminally differentiated cardiomyocytes, and beta-galactosidase in new cardiomy-
ocytes arising out of stem cells. The study demonstrated a progressive increase in
beta-galactosidase expressing cardiomyocytes following MI. During normal aging
up to one year, the percentage of GFP+ cardiomyocytes remained unchanged, indi-
cating that stem or precursor cells did not refresh uninjured cardiomyocytes at a
significant rate during this period of time. By contrast, after MI or pressure over-
load, the percentage of GFP+ cardiomyocytes decreased from 82.8% in heart tissue
from sham-treated mice to 67.5% in areas bordering a myocardial infarction, 76.6%
in areas away from a myocardial infarction, and 75.7% in hearts subjected to pres-
sure overload, indicating that stem cells or precursor cells had refreshed the cardio-
myocytes. Thus, the study inferred that CSCs might participate in the formation of
new cardiomyocytes after injury but not during the aging process. Using double
transgenic MerCreMer-ZEG mice, Chan et al. [ 21 ] also tracked the fate of adult
cardiomyocytes by the expression of GFP specifically induced in cardiomyocytes.
Upon experimental MI, a reduction in GFP expression in the myocardium was
observed, indicating the refreshment of cardiomyocytes by endogenous stem or pre-
cursor cells. Malliaras et al. [ 22 ] conducted genetic fate mapping to mark resident
myocytes in combination with long-term BrdU pulsing and studied the origins of
postnatal cardiomyogenesis in the normal, infarcted and cell-treated adult mamma-
lian heart. The study documented that myocyte replenishment occurs almost exclu-
sively through proliferation of small mononucleated adult cardiomyocytes in the
normal adult mouse heart, without any measurable contributions by endogenous
progenitors. They reported an annual endogenous cardiomyocyte turnover of 1.3%
(if we consider all cases of binucleation and polyploidization as instances where
cell cycle is activated abortively) to 4% (if we consider all measured DNA synthesis
as formation of new myocytes). The study however reported that after MI, new car-
diomyocytes arise from both, progenitors as well as pre-existing cardiomyocytes
and also transplantation of CDCs upregulate host cardiomyocyte cycling and
recruitment of endogenous progenitors, while improving heart function and increas-
ing viable myocardium.
Other school of thought proposes that cardiomyocytes are the progeny of resi-
dent CSCs, which control cell turnover physiologically and cardiac repair following
injury. Uchida et al. [ 23 ] generated triple-transgenic mice based on the tet-cre sys-
tem to identify descendants of cells that have expressed the stem cell marker Sca1.
They found a significant and lasting contribution of Sca1-derived cells to cardio-
myocytes during normal aging. Ischemic damage and pressure overload resulted in
S. Kaur et al.