Cardiomyogenic Potential of C-Kit + –Expressing Cells Derived From Neonatal and Adult Mouse Hearts

• Published in: Circulation (New York, N.Y.) Vol. 121; no. 18; pp. 1992 - 2000
• Main Authors: Zaruba, Marc-Michael, Soonpaa, Mark, Reuter, Sean, Field, Loren J.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 11.05.2010
• Subjects: Age Factors; Animals; Animals, Newborn; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cell Differentiation - physiology; Cells, Cultured; Coculture Techniques; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fibroblasts - cytology; Fibroblasts - physiology; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Green Fluorescent Proteins - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocytes, Cardiac - cytology; Myocytes, Cardiac - physiology; Phenotype; Proto-Oncogene Proteins c-kit - genetics; Vertebrates: cardiovascular system; Human; Myocardial infarction; stem cells; Stem cell; Rodentia; Cardiovascular disease; progenitor cells; Coronary heart disease; Myocardial disease; myocytes; Myocyte; Vertebrata; Mammalia; Newborn; Mouse; Animal; Molecular biology; Progenitor cell; cardiac
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.909093

Background— C-kit is a receptor tyrosine kinase family member expressed in hematopoietic stem cells. C-kit is also transiently expressed in cardiomyocyte precursors during development and in a rare cell population in the normal adult heart. In the present study, the cardiomyogenic potential of c-kit + cells isolated from normal neonatal, normal adult, and infarcted adult mouse hearts was evaluated. Methods and Results— Magnetic activated cell sorting was used to prepare c-kit + cells from the hearts of ACT-EGFP/MHC-nLAC double transgenic mice. These animals exhibit widespread enhanced green fluorescent protein (EGFP) expression and cardiomyocyte-restricted nuclear β-galactosidase activity, thus permitting simultaneous tracking of cell survival and differentiation. A subset of the c-kit + cells from double transgenic neonatal hearts acquired a cardiomyogenic phenotype when cocultured with fetal cardiomyocytes (2.4% of all EGFP + cells screened) but rarely when cultured alone or when cocultured with mouse fibroblasts (0.03% and 0.05% of the EGFP + cells screened, respectively). In contrast, c-kit + cells from normal adult double transgenic hearts failed to undergo cardiomyogenic differentiation when cocultured with nontransgenic fetal cardiomyocytes (>18 000 EGFP + cells screened) or when transplanted into normal or infarcted adult mouse hearts (14 EGFP + grafts examined). A single c-kit + cell from an infarcted double transgenic adult heart was observed to acquire a cardiomyogenic phenotype in coculture (>37 000 EGFP + cells screened). Conclusions— These data suggest that the ability of cardiac-resident c-kit + cells to acquire a cardiomyogenic phenotype is subject to temporal limitations or, alternatively, that the cardiomyogenic population is lost. Elucidation of the underlying molecular basis may permit robust cardiomyogenic induction in adult-derived cardiac c-kit + cells.