title: Impact of myocardial infarct proteins and oscillating pressure on the differentiation of mesenchymal stem cells: effect of acute myocardial infarction on stem cell differentiation.
abstract: 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.
authors.affiliation: National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea.
authors.forename: Sung-A
authors.initials: SA
authors.lastname: Chang
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Lee
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Choon-Soo
authors.initials: CS
authors.lastname: Lee
authors.forename: Keum-Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Joo-Yun
authors.initials: JY
authors.lastname: Won
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.forename: Kyung-Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yang
authors.forename: Won Il
authors.initials: WI
authors.lastname: Oh
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Yang
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Ho
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: 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
chemical_list: 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