Haemodynamic unloading increases the survival and affects the differentiation of cardiac stem cells after implantation into an infarcted heart.
OBJECTIVE
It has been anticipated that stem cell therapy is capable of repairing an injured heart but is currently limited by its marginal efficacy. We believe that mechanical stress due to haemodynamic loading may negate the therapeutic potency of stem cells and therefore investigated how haemodynamic unloading affects the survival and differentiation of stem cells after implantation into an infarcted heart.


METHODS
A left ventricular (LV) haemodynamic unloading model was implemented by heterotopic transplantation of an infarcted donor heart into another healthy mouse. An in situ infarcted heart with general haemodynamic loading was used as control. A total of 5 million cardiac stem cells expanded from green fluorescence protein (GFP)-transgenic mouse were intramyocardially implanted into the infarcted LVs of haemodynamically unloaded donor heart or general haemodynamic loaded heart. The survival and differentiation of the implanted cardiac stem cells were evaluated by histological analyses at 3 and 21 days after cell implantation (n = 5-6 in each time points per group).


RESULTS
Compared with the general haemodynamic loading condition, haemodynamic unloading of the infarcted hearts significantly improved the survival, increased the proliferation and inhibited the apoptosis of cardiac stem cells at 21 days after cell implantation (P < 0.05). In addition, the number of GFP(+)/Sca-1(+) cells was much higher in the unloaded hearts than in the loaded hearts at 21 days after cell implantation, although the difference was not statistically significant (5.67 ± 5.10 vs 0.75 ± 0.50, P = 0.051). Among the surviving GFP(+) donor cells 21 days after implantation, the expressions of platelet endothelial cell adhesion molecule-1, smooth muscle actin and sarcomeric alpha actin were ~7, 38 and 27% in the loaded heart and ~19, 14 and 55% in the unloaded heart, respectively.


CONCLUSIONS
Haemodynamic unloading favours the survival/engraftment of donor stem cells and affects their differentiation after implantation into an infarcted heart. Although further studies in a large animal model are required to investigate the functional benefits of haemodynamic unloading on stem cell therapy, we may temporarily unload the damaged heart to enhance cell engraftment and then load the heart again to induce the differentiation of stem cells.
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Hiroshi
H
Kurazumi
Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan litaoshe@nagasaki-u.ac.jp.
Tao-Sheng
TS
Li
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Yoshihiro
Y
Takemoto
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Ryo
R
Suzuki
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Akihito
A
Mikamo
Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan Department of Thoracic Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi, PR China.
Chang-Ying
CY
Guo
Institute of Laboratory Animals, Yamaguchi University, Yamaguchi, Japan.
Tomoaki
T
Murata
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Kimikazu
K
Hamano
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006439:Hemodynamics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000601:surgery*; D009206:Myocardium / Q000166:cytology*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*
Cardiac stem cells; Differentiation; Haemodynamic unloading; Survival