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(Circulation. 2004;110:2658-2665.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Differentiation of Bone Marrow Stromal Cells Into the Cardiac Phenotype Requires Intercellular Communication With Myocytes

Meifeng Xu, MD, PhD; Maqsood Wani, PhD; Yan-Shan Dai, MD, PhD; Jiang Wang, MD, PhD; Mei Yan, MD, PhD; Ahmar Ayub, DVM; Muhammad Ashraf, PhD

From the Department of Pathology and Laboratory Medicine (M.X., J.W., M.Y., A.A., M.A.), University of Cincinnati Medical Center, and the Department of Pediatrics (M.W., Y.-S.D.), University of Cincinnati, Children’s Hospital Medical Center, Cincinnati, Ohio.

Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0529. E-mail Muhammad.Ashraf{at}uc.edu

Received December 30, 2003; de novo received April 15, 2004; revision received June 1, 2004; accepted June 3, 2004.

Background— Bone marrow stromal cells (BMSCs) have the potential to differentiate into various cells and can transdifferentiate into myocytes if an appropriate cellular environment is provided. However, the molecular signals that underlie this process are not fully understood. In this study, we show that BMSC differentiation is dependent on communication with cells in their microenvironment.

Methods and Results— BMSCs were isolated from green fluorescent protein (GFP)–transgenic mice and cocultured with myocytes in a ratio of 1:40. Myocytes were obtained from neonatal rat ventricles. The differentiation of BMSCs in coculture was confirmed by immunohistochemistry, electron microscopy, and reverse transcription–polymerase chain reaction. Before coculturing, the BMSCs were negative for -actinin and exhibited a nucleus with many nucleoli. After 7-day coculture with myocytes, some BMSCs became -actinin–positive and formed gap junctions with native myocytes. However, BMSCs separated from myocytes by a semipermeable membrane were still negative for -actinin. Transdifferentiated myocytes from BMSCs were microdissected from cocultures by laser captured microdissection to determine the changes in gene expression. BMSCs cocultured with myocytes expressed mouse cardiac transcription factor GATA-4.

Conclusions— When cocultured with myocytes, BMSCs can transdifferentiate into cells with a cardiac phenotype. Differentiated myocytes express cardiac transcription factors GATA-4 and myocyte enhancer factor-2. The transdifferentiation processes rely on intercellular communication of BMSCs with myocytes.

Key Words: myocytes • stem cells • signal transduction • genetics

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