Author + information
- Received July 19, 2016
- Revision received August 18, 2016
- Accepted September 6, 2016
- Published online December 6, 2016.
- Shathiyah Kulandavelu, PhDa,
- Vasileios Karantalis, MDa,
- Julia Fritsch, BSa,
- Konstantinos E. Hatzistergos, PhDa,
- Viky Y. Loescher, MDa,
- Frederic McCall, BSa,
- Bo Wang, MDa,
- Luiza Bagno, PhDa,
- Samuel Golpanian, MDa,
- Ariel Wolf, BSa,
- Justin Grenet, BSa,
- Adam Williams, MDa,
- Aaron Kupina,
- Aaron Rosenfelda,
- Sadia Mohsin, PhDb,
- Mark A. Sussman, PhDb,
- Azorides Morales, MDc,
- Wayne Balkan, PhDa,c and
- Joshua M. Hare, MDa,c,∗ ()
- aThe Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida
- bBiology Department and Integrated Regenerative Research Institute, San Diego State University, San Diego, California
- cDepartment of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- ↵∗Reprint requests and correspondence:
Dr. Joshua M. Hare, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Biomedical Research Building, 1501 N.W. 10th Avenue, Room 824, P.O Box 016960 (R125), Miami, Florida 33101.
Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties.
Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).
Methods Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration.
Results Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7% vs. −8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005).
Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.
Dr. Hare is supported by the National Institutes of Health (NIH) grant R01 HL084275; and NIH grants R01 HL107110, R01 HL110737, and 5UM HL113460; and is a board member and consults for Vestion Inc. Dr. Karantalis was supported by a postdoctoral fellowship award from the American Heart Association. Dr. Sussman is supported by NIH grants: R01HL067245, R37HL091102, R01HL105759, R01HL113647, R01HL117163, P01HL085577, and R01HL122525; as well as an award from the Fondation Leducq. Dr. Hatzistergos is a member of the scientific advisory board; and consults for and has equity in Vestion Inc. Vestion did not contribute funding to this study. Dr. Sussman is cofounder of CardioCreate, Inc. CardioCreate did not contribute funding to this study. Dr. Morales has received U.S. patent royalties from Sakura Finetek. Sakura Finetek, USA did not contribute funding to this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Kulandavelu and Karantalis contributed equally to this work.
- Received July 19, 2016.
- Revision received August 18, 2016.
- Accepted September 6, 2016.
- American College of Cardiology Foundation