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First published online April 10, 2008
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2007-0708v1
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Submitted on August 30, 2007
Accepted on March 28, 2008

TRANSLATIONAL AND CLINICAL RESEARCH

Impact of Myocardial Infarct Proteins and Oscillating Pressure on the Differentiation of Mesenchymal Stem Cells: Effect of Acute Myocardial Infarction on Stem Cell Differentiation

Sung A Chang 1, Eun Ju Lee 2, Hyun Jae Kang 3, Shu Ying Zhang 4, Ji Hyun Kim 4, Lian Li 4, Seock Won Youn 4, Choon Soo Lee 4, Keum Hyun Kim 4, Joo Yun Won 4, Jong Woo Sohn 5, Kyung Woo Park 3, Hyun Jai Cho 3, Sung Eun Yang 6, Won Il Oh 6, Yoon Sun Yang 6, Won Kyung Ho 5, Young Bae Park 3, Hyo Soo Kim 3*

1 National Research Laboratory for Cardiovascular Stem Cells, Department of Internal Medicine, Seoul National University College of Medicine; Seoul, Korea
2 National Research Laboratory for Cardiovascular Stem Cells, Innovative Research Institute for Cell Therapy (IRICT), Seoul National University Hospital; Seoul, Korea
3 National Research Laboratory for Cardiovascular Stem Cells, Department of Internal Medicine, Seoul National University College of Medicine; Innovative Research Institute for Cell Therapy (IRICT), Seoul National University Hospital; Seoul, Korea
4 National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
5 National Research Laboratory for Cell Physiology, Department of Physiology, Seoul National University College of Medicine, Seoul, Korea
6 Medipost Inc.; Seoul, Korea

* To whom correspondence should be addressed. E-mail: hyosoo{at}snu.ac.kr.


  Abstract

Stem cell transplantation in acute myocardial infarction (AMI) 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 beating heart with acute ischemia, as follows; 1) myocardial proteins or serum obtained from rat of sham operation or 2) myocardial proteins or serum from rats of AMI, 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. It was also induced by application of oscillating pressure on 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 (TGF-{beta}1) or bone morphogenic proteins (BMP-2). In vitro cellular and electro-physiologic experiments showed that these differentiated MSCs expressing cardiomyocyte-specific markers, were able to make coupling with cardiomyocytes, but not to do self-beating.

Pathophysiologic significance of in vitro results was confirmed using 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.

______________________________________________________________________________

Author contributions: S.C.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing; E.J.L.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing; H.K.: Conception and design, Data analysis and interpretation; S.Z.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation; J.K.: Provision of study material or patients, Collection and/or assembly of data, Data analysis and interpretation; L.L.: Provision of study material or patients, Collection and/or assembly of data, Data analysis and interpretation; S.Y.: Provision of study material or patients, Collection and/or assembly of data, Data analysis and interpretation; C.L.: Provision of study material or patients, Collection and/or assembly of data; K.K.: Provision of study material or patients, Collection and/or assembly of data; J.W.: Provision of study material or patients, Collection and/or assembly of data; J.S.: Provision of study material or patients, Collection and/or assembly of data, Data analysis and interpretation; K.P.: Data analysis and interpretation; H.C.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation; S.Y.: Provision of study material or patients; W.I.O.: Provision of study material or patients; Y.S.Y.: Provision of study material or patients; W.H.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation; Y.P.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation; H.K.: Conception and design, Data analysis and interpretation, Manuscript writing, Final approval of manuscript.

S.-A. Chang and E.J. Lee contributed equally to this work.

 Key Words. Cardiomyocytes, Mesenchymal stem cells, Differentiation, Acute myocardial infarction






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