Safety and Efficacy of Allogeneic Cell Therapy in Infarcted Rats Transplanted with Mismatched Cardiosphere-Derived Cells
Background—Cardiosphere-derived cells (CDCs) are an attractive cell type for tissue regeneration, and autologous CDCs are being tested clinically. However, autologous therapy necessitates patient-specific tissue harvesting and cell processing, with delays to therapy and possible variations in cell potency. The use of allogeneic CDCs, if safe and effective, would obviate such limitations. We compared syngeneic and allogeneic CDC transplantation in rats from immunologically-mismatched inbred strains.
Methods and Results—In vitro, CDCs expressed MHC class I but not class II antigens or B7 costimulatory molecules. In mixed lymphocyte co-cultures, allogeneic CDCs elicited negligible lymphocyte proliferation and inflammatory cytokine secretion. In vivo, syngeneic and allogeneic CDCs survived at similar levels in the infarcted rat heart 1 week after delivery, but few syngeneic (and even fewer allogeneic) CDCs remained at 3 weeks. Allogeneic CDCs induced a transient, mild, local immune reaction in the heart, without histologically-evident rejection or systemic immunogenicity. Improvements in cardiac structure and function, sustained for 6 months, were comparable with syngeneic and allogeneic CDCs. Allogeneic CDCs stimulated endogenous regenerative mechanisms (cardiomyocyte cycling, recruitment of c-kit+ cells, angiogenesis) and increased myocardial VEGF, IGF-1 and HGF equally with syngeneic CDCs.
Conclusions—Allogeneic CDC transplantation without immunosuppression is safe, promotes cardiac regeneration and improves heart function in a rat myocardial infarction model, mainly through stimulation of endogenous repair mechanisms. This indirect mechanism of action rationalizes the persistence of benefit despite the evanescence of transplanted cell survival. This work motivates the testing of allogeneic human CDCs as a potential off-the-shelf product for cellular cardiomyoplasty.
- Received May 8, 2011.
- Accepted October 27, 2011.
- Copyright © 2011, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited