Recent studies have demonstrated that direct cell-to-cell interaction is one of the microenvironment factors for transdifferentiation of adult stem cells into cardiomyocytes. We investigated whether transdifferentiation of mesenchymal stem cells (MSCs) into cardiomyocytes was dependent on developmental stages of cocultured cardiomyocytes, and direct cell-to-cell interaction was essential for transdifferentiation. MSCs were isolated from adult rat and cocultured in four different ways: (1) with neonatal cardiomyocytes, (2) with adult cardiomyocytes, (3) with neonatal cardiomyocytes on the cell culture inserts, and (4) with the conditioned medium from neonatal cardiomyocytes. After 5 days of coculture with neonatal cardiomyocytes, 9.40±1.15% of 1,1′-dioctadecyl-1-3,3,3′,3′-tetramethylindocarbocyanine perchlorate labeled MSCs expressed sarcomeric-α-actinin. Immunocytochemistry showed that only these MSCs expressed the cardiac markers and were not observed with other coculture condition as well as conditioned medium. Calcein-AM labeling of cardiomyocytes showed gap junctional communication between 56.1±2.0% of MSCs (24 h after labeling, n=5) and neonatal cardiomyocytes. These findings suggest that MSCs are capable of differentiating into cardiomyocytes when directly cocultured with neonatal cardiomyocytes by cell-to-cell interaction, but not with adult cardiomyocytes or conditioned medium.
This work was supported by the Brain Korea 21 project and the Korea Health 21 R&D project, Ministry of Health and Welfare, Republic of Korea (Dr. Lim, 01-PJ10-PG8-01EC01-0027).
Makino S, Fukuda K, Miyoshi S et al (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705PubMedGoogle Scholar
Lough J, Barron M, Brogley M et al (1996) Combined BMP-2 and FGF-4, but neither factor alone, induces cardiogenesis in non-precardiac embryonic mesoderm. Dev Biol 178:198–202CrossRefPubMedGoogle Scholar
Wang J-S, Shum-Tim D, Galipeau J et al (2000) Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg 120:999–1006CrossRefPubMedGoogle Scholar
Badorff C, Brandes RP, Popp R et al (2003) Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 107:1024–1032CrossRefPubMedGoogle Scholar
Iijima Y, Nagai T, Mizukami M et al (2003) Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes. FASEB J 17:1361–1363PubMedGoogle Scholar
Fukuhara S, Tomita S, Yamashiro S et al (2003) Direct cell–cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro. J Thorac Cardiovasc Surg 125:1470–1480CrossRefPubMedGoogle Scholar
Muller JG, Thompson JT, Edmonson AM et al (2002) Differential regulation of the cardiac sodium calcium exchanger promoter in adult and neonatal cardiomyocytes by Nkx2.5 and serum response factor. J Mol Cell Cardiol 34:807–821CrossRefPubMedGoogle Scholar
Terada N, Hamazaki T, Oka M et al (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545CrossRefPubMedGoogle Scholar
Lagasse E, Connors H, Al-Dhalimy M et al (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6:1229–1234CrossRefPubMedGoogle Scholar
Shake JG, Gruber PJ, Baumgartner WA et al (2002) Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects, Ann Thorac Surg 73:1919–1925CrossRefPubMedGoogle Scholar