Impact of myocardial infarct proteins and oscillating pressure on the differentiation of mesenchymal stem cells: effect of acute myocardial infarction on stem cell differentiation.
Stem cell transplantation in acute myocardial infarction (AMI) has emerged as a promising therapeutic option. We evaluated the impact of AMI on mesenchymal stem cell (MSC) differentiation into cardiomyocyte lineage. Cord blood-derived human MSCs were exposed to in vitro conditions simulating in vivo environments of the beating heart with acute ischemia, as follows: (a) myocardial proteins or serum obtained from sham-operated rats, and (b) myocardial proteins or serum from AMI rats, with or without application of oscillating pressure. Expression of cardiac-specific markers on MSCs was greatly induced by the infarcted myocardial proteins, compared with the normal proteins. It was also induced by application of oscillating pressure to MSCs. Treatment of MSCs with infarcted myocardial proteins and oscillating pressure greatly augmented expression of cardiac-specific genes. Such expression was blocked by inhibitor of transforming growth factor beta(1) (TGF-beta(1)) or bone morphogenetic protein-2 (BMP-2). In vitro cellular and electrophysiologic experiments showed that these differentiated MSCs expressing cardiomyocyte-specific markers were able to make a coupling with cardiomyocytes but not to selfbeat. The pathophysiologic significance of in vitro results was confirmed using the rat AMI model. The protein amount of TGF-beta(1) and BMP-2 in myocardium of AMI was significantly higher than that in normal myocardium. When MSCs were transplanted to the heart and analyzed 8 weeks later, they expressed cardiomyocyte-specific markers, leading to improved cardiac function. These in vitro and in vivo results suggest that infarct-related biological and physical factors in AMI induce commitment of MSCs to cardiomyocyte-like cells through TGF-beta/BMP-2 pathways.
Chang
Sung-A
SA
National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea.
Lee
Eun Ju
EJ
Kang
Hyun-Jae
HJ
Zhang
Shu-Ying
SY
Kim
Ji-Hyun
JH
Li
Lian
L
Youn
Seock-Won
SW
Lee
Choon-Soo
CS
Kim
Keum-Hyun
KH
Won
Joo-Yun
JY
Sohn
Jong-Woo
JW
Park
Kyung-Woo
KW
Cho
Hyun-Jai
HJ
Yang
Sung-Eun
SE
Oh
Won Il
WI
Yang
Yoon Sun
YS
Ho
Won-Kyung
WK
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009203:Myocardial Infarction / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009991:Oscillometry; D010641:Phenotype; D051381:Rats; D013234:Stem Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014471:Umbilical Veins / Q000378:metabolism
C525718:BMP2 protein, human; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002118:Calcium