Author + information
- Received November 28, 2011
- Revision received March 9, 2012
- Accepted April 2, 2012
- Published online October 2, 2012.
- Sadia Mohsin, PhD⁎,
- Mohsin Khan, PhD⁎,
- Haruhiro Toko, MD, PhD⁎,
- Brandi Bailey, PhD⁎,
- Christopher T. Cottage, MS⁎,
- Kathleen Wallach, BS⁎,
- Divya Nag†,
- Andrew Lee, BS†,
- Sailay Siddiqi, MD⁎,
- Feng Lan, PhD†,
- Kimberlee M. Fischer, PhD⁎,
- Natalie Gude, PhD⁎,
- Pearl Quijada, MS⁎,
- Daniele Avitabile, PhD⁎,
- Silvia Truffa, BS⁎,
- Brett Collins, BS⁎,
- Walter Dembitsky, MD‡,
- Joseph C. Wu, MD, PhD† and
- Mark A. Sussman, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Mark A. Sussman, SDSU Heart Institute and Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, California 92182
Objectives The goal of this study was to demonstrate the enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for the treatment of myocardial infarction.
Background Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation, and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration.
Methods hCPCs isolated from the myocardium of heart failure patients undergoing left ventricular assist device implantation were engineered to express green fluorescent protein (hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential were performed with immunocompromised mice by using intramyocardial adoptive transfer injection after infarction. Myocardial structure and function were monitored by echocardiographic and hemodynamic assessment for 20 weeks after delivery. hCPCe and hCPCeP expressing luciferase were observed by using bioluminescence imaging to noninvasively track persistence.
Results hCPCeP exhibited augmentation of reparative potential relative to hCPCe control cells, as shown by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrated increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe was revealed by bioluminescence imaging at up to 8 weeks post-delivery.
Conclusions Genetic engineering of hCPCs with Pim-1 enhanced repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of hCPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in pre-clinical settings.
Dr. Sussman was supported by National Institutes of Health grants R21HL102714, R01HL067245, R37HL091102, P01HL085577, RC1HL100891, R21HL102613, R21HL104544, RO1 HL113656, and R01HL105759. Dr. Wu was supported by National Institutes of Health grants RC1HL100891 and R01EB009689. Dr. Dembitsky is a lecturer and has received grant support from Thoratec. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received November 28, 2011.
- Revision received March 9, 2012.
- Accepted April 2, 2012.
- American College of Cardiology Foundation