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(Circulation. 2007;115:896-908.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Regenerative Potential of Cardiosphere-Derived Cells Expanded From Percutaneous Endomyocardial Biopsy Specimens

Rachel Ruckdeschel Smith, BS^*; Lucio Barile, PharmD^*; Hee Cheol Cho, PhD^*; Michelle K. Leppo, BS; Joshua M. Hare, MD; Elisa Messina, MD, PhD; Alessandro Giacomello, MD, PhD; M. Roselle Abraham, MD; Eduardo Marbán, MD, PhD

From the Division of Cardiology (R.R.S., L.B., H.C.C., M.K.L., J.M.H., E. Messina, M.R.A., E. Marbán), Johns Hopkins University, Baltimore, Md, and Department of Experimental Medicine, Pasteur Institute, Cenci Bolognetti Foundation, University La Sapienza, Rome, Italy (L.B., E. Messina, A.G.).

Correspondence to Eduardo Marbán, MD, 720 Rutland Ave, Ross 858, Baltimore, MD 21205. E-mail marban{at}jhmi.edu

Received July 28, 2006; accepted November 27, 2006.

Background— Ex vivo expansion of resident cardiac stem cells, followed by delivery to the heart, may favor regeneration and functional improvement.

Methods and Results— Percutaneous endomyocardial biopsy specimens grown in primary culture developed multicellular clusters known as cardiospheres, which were plated to yield cardiosphere-derived cells (CDCs). CDCs from human biopsy specimens and from comparable porcine samples were examined in vitro for biophysical and cytochemical evidence of cardiogenic differentiation. In addition, human CDCs were injected into the border zone of acute myocardial infarcts in immunodeficient mice. Biopsy specimens from 69 of 70 patients yielded cardiosphere-forming cells. Cardiospheres and CDCs expressed antigenic characteristics of stem cells at each stage of processing, as well as proteins vital for cardiac contractile and electrical function. Human and porcine CDCs cocultured with neonatal rat ventricular myocytes exhibited biophysical signatures characteristic of myocytes, including calcium transients synchronous with those of neighboring myocytes. Human CDCs injected into the border zone of myocardial infarcts engrafted and migrated into the infarct zone. After 20 days, the percentage of viable myocardium within the infarct zone was greater in the CDC-treated group than in the fibroblast-treated control group; likewise, left ventricular ejection fraction was higher in the CDC-treated group.

Conclusions— A method is presented for the isolation of adult human stem cells from endomyocardial biopsy specimens. CDCs are cardiogenic in vitro; they promote cardiac regeneration and improve heart function in a mouse infarct model, which provides motivation for further development for therapeutic applications in patients.

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