Enhanced recovery of mechanical function in the canine heart by seeding an extracellular matrix patch with mesenchymal stem cells committed to a cardiac lineage

doi:10.1152/ajpheart.00219.2008

Enhanced recovery of mechanical function in the canine heart by seeding an extracellular matrix patch with mesenchymal stem cells committed to a cardiac lineage

Irina A. Potapova,¹ Sergey V. Doronin,¹ Damon J. Kelly,¹^,2 Amy B. Rosen,²^,3 Adam J. T. Schuldt,²^,3 Zhongju Lu,¹^,2 Paul V. Kochupura,⁴ Richard B. Robinson,⁵ Michael R. Rosen,⁵^,6 Peter R. Brink,¹^,2 Glenn R. Gaudette,⁷ and Ira S. Cohen¹^,2

¹Department of Physiology and Biophysics, ²Institute of Molecular Cardiology, ³Department of Biomedical Engineering, and ⁴Department of Surgery, Stony Brook University, New York; ⁵Center for Molecular Therapeutics and Departments of Pharmacology and ⁶Pediatrics, Columbia University, New York, New York; and ⁷Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, Massachusetts

Submitted 1 March 2008 ; accepted in final form 30 September 2008

The need to regenerate tissue is paramount, especially for theheart that lacks the ability to regenerate after injury. Theurinary bladder extracellular matrix (ECM), when used to repaira right ventricular defect, successfully regenerated some mechanicalfunction. The objective of the current study was to determinewhether the regenerative effect of ECM could be improved byseeding the patch with human mesenchymal stem cells (hMSCs)enhanced to differentiate down a cardiac linage. hMSCs wereused to form three-dimensional spheroids. The expression ofcardiac proteins was determined in cells exposed to the spheroidformation and compared with nonmanipulated hMSCs. To determinewhether functional calcium channels were present, the cellswere patch clamped. To evaluate the ability of these cells toregenerate mechanical function, the spheroids were seeded onECM and then implanted into the canine heart to repair a full-thicknessright ventricular defect. As a result, many of the cells spreadingfrom the spheroids expressed cardiac-specific proteins, includingsarcomeric ${alpha}$ -actinin, cardiotin, and atrial natriuretic peptide,as well as the cell cycle markers cyclin D1 and proliferatingcell nuclear antigen. A calcium current similar in amplitudeto that of ventricular myocytes was present in 16% of the cells.The cardiogenic cell-seeded scaffolds increased the regionalmechanical function in the canine heart compared with the unmanipulatedhMSC-seeded scaffolds. In addition, the cells prelabeled withfluorescent markers demonstrated myocyte-specific actinin stainingwith sarcomere spacing similar to that of normal myocytes. Inconclusion, the spheroid-derived cells express cardiac-specificproteins and demonstrate a calcium current similar to adultventricular myocytes. When these cells are implanted into thecanine heart, some of these cells appear striated and mechanicalfunction is improved compared with the unmanipulated hMSCs.Further investigation will be required to determine whetherthe increased mechanical function is due to a differentiationof the cardiogenic cells to myocytes or to other effects.

human mesenchymal stem cells; myocyte structure; cardiac contractile function; myogenesis; cardiac regeneration; myocardium; heart failure

Address for reprint requests and other correspondence: G. R. Gaudette, Dept. of Biomedical Engineering, Worcester Polytechnic Institute, 100 Institute Rd., Worcester, MA 01609 (e-mail: gaudette{at}wpi.edu)