Safety and Efficacy of Allogeneic Cell Therapy in Infarcted Rats Transplanted With Mismatched Cardiosphere-Derived Cells

Abstract

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.

Cadaveric cardiosphere-derived cells can maintain regenerative capacity and improve the heart function of cardiomyopathy

“…9 Furthermore, allogeneic CDC transplantation without immunosuppression induces only a transient mild local immune reaction in a rat myocardial infarction (MI) model. [10][11] The CADUCEUS (CArdiosphere-Derived aUtologous Stem CElls to Reverse ventricUlar dySfunction) trial proved the efficacy and safety of CDC transplantation for treatment of MI. 12 Recently, Mohammad et al found that CDC treatment prevents functional deterioration, attenuates oxidative stress, promotes cardiomyocyte proliferation, and reduces mortality in a transgenic mouse model of dilated cardiomyopathy (DCM).…”

Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

“…Allogeneic cell therapy has the additional advantage that it avoids variations of cell efficacy attributable to patient age or comorbidities, plus the risks and costs of patient‐specific tissue harvesting and cell processing. Although immune rejection is a possible disadvantage, allogeneic mesenchymal stem cells25 and CDCs (http://clinicaltrials.gov/ct2/show/NCT01458405) have been used in various early‐phase clinical trials of heart disease without safety concerns,25 consistent with preclinical studies indicating that allogeneic cell therapy without immunosuppression is safe and effective 3, 14, 20, 26. Indeed, our study demonstrates only nonsignificant local inflammatory response and the absence of circulating alloreactive antibodies with long‐term follow‐up after the administration of allo‐CDCs.…”

“…CDCs have been argued to be cardiac progenitor cells,29, 30, 31 but that feature of CDCs is an epiphenomenon when it comes to mechanism of action. In the extreme, allo‐CDCs are cleared completely within several weeks, but their functional and structural benefits persist at least 6 months 14. Thus, long‐term transplanted cell survival is not required for sustained benefit 32.…”

“…Finally, our phenotyping ended 2 months after cell treatment in this study. Although our previous work indicates that the benefits of CDCs can last even longer,10, 14 more‐extended evaluation would be valuable, particularly in terms of hard clinical endpoints, such as progression to heart failure.…”

Isolation, Characterization, and Spatial Distribution of Cardiac Progenitor Cells in the Sheep Heart

“…The ability to isolate higher numbers of c-kit+cells from some older individuals may be a consequence of the medical condition of the patient [16]. The expression of c-kit has been identified on cardiovascular progenitors, cardiospheres and cardiosphere-derived cells (CDCs) [27,28]. In rats, transplantation of progenitor cells expressing c-kit improves cardiac function [28] and the c-kit+cardiac stem cells are beneficial when administered in human clinical trials [16].…”