Safety of Intracoronary Infusion of 20 Million C-Kit Positive Human Cardiac Stem Cells in Pigs

• Type of Material: Article
• Authors: Matthew C. L. Keith, University of Louisville; Xian-Liang Tang, University of Louisville; Yukichi Tokita, University of Louisville; Qian-hong Li, University of Louisville; Shahab Ghafghazi, University of Louisville; Joseph Moore, University of Louisville; Kyung U. Hong, University of Louisville; Brandon Elmore, University of Louisville; Alok Amraotkar, University of Louisville; Brian L. Ganzel, University of Louisville; Kendra Grubb, Emory University; Michael P. Flaherty, University of Louisville; Gregory Hunt, University of Louisville; Bathri Vajravelu, University of Louisville; Marcin Wysoczynski, University of Louisville; Roberto Bolli, University of Louisville
• Language: English
• Date: 2015-04-23
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Keith et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0124227
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 10
• Issue: 4
• Start Page: e0124227
• End Page: e0124227
• Grant/Funding Information: This study was funded by NIH grants P01-HL78825 and 1 UM1 HL-113530.
• Keywords: EFFICACY; PORCINE MODEL; LEFT-VENTRICULAR FUNCTION; Science & Technology; ACUTE MYOCARDIAL-INFARCTION; INJECTION; Multidisciplinary Sciences; REGENERATION; PROGENITOR CELLS; TRANSPLANTATION; Science & Technology - Other Topics; DELIVERY
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: There is mounting interest in using c-kit positive human cardiac stem cells (c-kit^pos hCSCs) to repair infarcted myocardium in patients with ischemic cardiomyopathy. A recent phase I clinical trial (SCIPIO) has shown that intracoronary infusion of 1 million hCSCs is safe. Higher doses of CSCs may provide superior reparative ability; however, it is unknown if doses >1 million cells are safe. To address this issue, we examined the effects of 20 million hCSCs in pigs. Methods: Right atrial appendage samples were obtained from patients undergoing cardiac surgery. The tissue was processed by an established protocol with eventual immunomagnetic sorting to obtain in vitro expanded hCSCs. A cumulative dose of 20 million cells was given intracoronarily to pigs without stop flow. Safety was assessed by measurement of serial biomarkers (cardiac: troponin I and CK-MB, renal: creatinine and BUN, and hepatic: AST, ALT, and alkaline phosphatase) and echocardiography pre- and post-infusion. hCSC retention 30 days after infusion was quantified by PCR for human genomic DNA. All personnel were blinded as to group assignment. Results: Compared with vehicle-treated controls (n=5), pigs that received 20 million hCSCs (n=9) showed no significant change in cardiac function or end organ damage (assessed by organ specific biomarkers) that could be attributed to hCSCs (P>0.05 in all cases). No hCSCs could be detected in left ventricular samples 30 days after infusion. Conclusions: Intracoronary infusion of 20 million c-kit positive hCSCs in pigs (equivalent to ∼40 million hCSCs in humans) does not cause acute cardiac injury, impairment of cardiac function, or liver and renal injury. These results have immediate translational value and lay the groundwork for using doses of CSCs >1 million in future clinical trials. Further studies are needed to ascertain whether administration of >1 million hCSCs is associated with greater efficacy in patients with ischemic cardiomyopathy.