Cardiosphere-derived cells do not improve cardiac function in rats with cardiac failure

Abstract

BackgroundHeart failure represents an important public health issue due to its high costs and growing incidence worldwide. Evidence showing the regenerative potential of postmitotic heart tissue has suggested the existence of endogenous cardiac stem cells in adult hearts. Cardiosphere-derived cells (CDC) constitute a candidate pool of such cardiac stem cells. Previous studies using acute myocardial infarction (MI) models in rodents demonstrated an improvement in cardiac function after cell therapy with CDC. We evaluated the therapeutic potential of CDC 60 days after MI in a rat model.MethodsCDC were obtained from human discarded myocardial tissue and rat hearts by enzymatic digestion with collagenase II. At 10–15 days after isolation, small, round, phase-bright cells (PBCs) appeared on top of the adherent fibroblast-like cells. The PBCs were collected and placed on a nonadherent plate for 2 days, where they formed cardiospheres which were then transferred to adherent plates, giving rise to CDC. These CDC were characterized by flow cytometry. Wistar rats were submitted to MI through permanent occlusion of the anterior descending coronary artery. After 60 days, they were immunosuppressed with cyclosporine A during 10 days. On the third day, infarcted animals were treated with 5 × 105 human CDC (hCDC) or placebo through intramyocardial injection guided by echocardiogram. Another group of animals was treated with rat CDC (rCDC) without immunosuppression. hCDC and rCDC were stably transduced with a viral construct expressing luciferase under control of a constitutive promoter. CDC were then used in a bioluminescence assay. Functional parameters were evaluated by echocardiogram 90 and 120 days after MI and by Langendorff at 120 days.ResultsCDC had a predominantly mesenchymal phenotype. Cell tracking by bioluminescence demonstrated over 85% decrease in signal at 5–7 days after cell therapy. Cardiac function evaluation by echocardiography showed no differences in ejection fraction, end-diastolic volume, or end-systolic volume between groups receiving human cells, rat cells, or placebo. Hemodynamic analyses and infarct area quantification confirmed that there was no improvement in cardiac remodeling after cell therapy with CDC.ConclusionOur study challenges the effectiveness of CDC in post-ischemic heart failure.

Collagen type I and hyaluronic acid based hybrid scaffolds for heart valve tissue engineering

“…Increasing the crosslinking density and incorporation of the HA network resulted in a fivefold increase in the bending modulus from 150 to 1660 kPa. Provided that the sinus and aortic wall are stiffer than the aortic valve leaflet, hybrid scaffolds have the potential to be further developed into an integrated design mimicking the entire aortic root (including leaflets). CDCs attachment was mainly affected by the number of available cell‐binding sites (not engaged in the crosslinking process).…”

A Bibliometric and Visualized Analysis of Cardiac Regeneration Over a 20-Year Period

“…The work of Makkar published in Lancet in 2012, also the most prominent study in cluster #5, proved that intracoronary infusion of autologous CDCs after MI was able to achieve the therapeutic goal of cardiac regeneration to a certain extent (23). However, some of the later studies did not observe similar results in the rats, large animals, or humans, and only modest or unnoticeable changes were found in cardiac function after injection of CDCs (10,24,25); therefore, the attention of CDCs has gradually decreased, and no other influential articles explaining its value in cardiac regeneration have been published in the last 5 years.…”

Combining stem cells in myocardial infarction: The road to superior repair?

“…45 In contrast, a recent study intramyocardially injecting CDCs in rats with MI did not increase LVEF compared to control. 46 Despite contradictory results in preclinical studies, the CADUCEUS clinical trial was initiated performing intracoronary infusion of CDCs in patients with MI. 75,76 No improvement in LVEF was observed at 12-month follow-up.…”

“…Transplantation of CDCs improved both infarct wall thickness and LVEF in a mouse model of chronic MI 45 . In contrast, a recent study intramyocardially injecting CDCs in rats with MI did not increase LVEF compared to control 46 . Despite contradictory results in preclinical studies, the CADUCEUS clinical trial was initiated performing intracoronary infusion of CDCs in patients with MI 75,76 .…”