Development of a peptide-targeted, myocardial ischemia-homing, mesenchymal stem cell

Abstract

Directing stem cells to the heart is critical in producing an effective cell therapy for myocardial infarction (MI). Mesenchymal stem cells (MSCs) offer an exquisite drug delivery platform with environment-sensing cytokine release and MSCs have shown therapeutic potential in MI. Peptide-based targeting offers a novel method to increase cell homing, wherein MI-specific peptides, identified by phage display, are synthesized with a palmitic acid tail to facilitate cell membrane integration. Phage-peptides were screened in a mouse MI model and four peptides (CRPPR, CRKDKC, KSTRKS, and CARSKNKDC) were selected and synthesized as palmitated derivatives for further investigation. Cell coating was optimized and coating persistence and cytotoxicity were evaluated. MSCs were coated with peptides, injected into mice with MI, and MSCs in the heart quantified. Greater numbers of MSCs were found in heart of animals treated with the peptide-coated MSCs compared to uncoated controls. MSC numbers had positive correlation with MI severity in peptide-coated cells but a negative correlation in MSCs alone. A transient cell coating (“painting”) method has been developed that labels cells efficiently, non-toxically and increases cell localization in MI hearts.

Keywords::

• Cell targeting
• peptide-based cell targeting
• mesenchymal stem cell
• cardiac repair
• cell therapy
• targeted cell therapy
• cardiac cell therapy

Acknowledgments

The authors are very appreciative of the advice and support provided for this research by Erkki Ruoslahti, MD, PhD, and his laboratory at the Burnham Institute for Medical Research, USCD, La Jolla, CA. Jenifer Mikulan and Amad Awadallah are gratefully acknowledged for histology processing, as are Margie Harris and Donald Lennon for isolating and supplying MSCs.

Declaration of interest

J.W., A.I.C., J.E.D. all received stock in Biotime Inc. for the sale of Cell Targeting LLC. Patent Application #61/184,682. This research was supported by NIH grant AR49785, DARPA Contract No. W911NF-06-0075 and the Clinical Tissue Engineering Center (Cleveland, OH).