Cardiospheres reverse adverse remodeling in chronic rat myocardial infarction: roles of soluble endoglin and Tgf-β signaling

Abstract

Self-assembling heart-derived stem cell clusters named cardiospheres (CSps) improve function and attenuate remodeling in rodent models of acute myocardial infarction. The effects of CSps in chronically remodeled myocardium post-MI, and the underlying mechanisms, remain unknown. One month after permanent coronary ligation, rats were randomly assigned to injection of vehicle (controls) or CSps in the peri-infarct area. One month post-injection, CSps increased left ventricular function, reduced scar mass and collagen density, and enhanced vascularity within the infarct zone compared to controls. Immunoblots revealed Tgfβ-1/smad cascade downregulation and an increase in soluble endoglin post-CSp injection. Six months post-transplantation, left ventricular function further improved and cardiomyocyte hypertrophy was attenuated in the CSp-treated group. In vitro, co-culture of CSps with fibroblasts recapitulated the suppression of the Tgf-β1/smad pathway changes, responses which were blunted by neutralizing antibody against endoglin. Thus, cardiosphere transplantation enhances angiogenesis and reduces fibrosis in chronically infarcted myocardium, leading to partial reversal of cardiac dysfunction. The underlying mechanism involves inhibition of Tgf-β1/smad signaling by CSp-secreted soluble endoglin.

C1q/tumor necrosis factor-related protein-6 attenuates post-infarct cardiac fibrosis by targeting RhoA/MRTF-A pathway and inhibiting myofibroblast differentiation

“…Members of TGF-b family are markedly induced in the infarct myocardium and play a key role in fibrotic remodeling of post-MI hearts, mediating fibroblast activation, proliferation, migration, and ECM deposition [2,41]. TGF-b1 is the prevalent isoform and is found almost ubiquitously [9].…”

Targeting chronic cardiac remodeling with cardiac progenitor cells in a murine model of ischemia/reperfusion injury

“…Recently, it was demonstrated that CPC reduced fibroblast proliferation and attenuated pro-fibrotic signaling in a rat model of chronic MI [35]. This notion is supported by the observed long term improved left ventricular remodeling upon CPC treatment [14, 15, 36]. Several reports suggest that early changes in matrix remodeling are detected with a higher sensitivity with measurements of regional wall motion parameters by speckle tracking analysis [37–40].…”

“…and Tseliou et al . demonstrated an improvement of the LVEF upon treatment with CPC in a rat model of chronic cardiac injury with application of CPC 4 weeks after ischemic injury [14, 15]. Likewise, it was demonstrated that CPC treatment applied 7 days after permanent ligation of the LAD in mice resulted in improvement of LVEF and a lowering of the ventricular scar burden [17].…”

“…One particular reason for the difficulty to translate functional outcomes from small to large animal models (and eventually to the clinic) is that cell therapy in small animal models is predominantly investigated in an acute myocardial injury setting [13]. Only a limited number of studies [14–17] tested stem cell therapy in small animals during chronic cardiac remodeling before switching to pre-clinical large animal research. To allow for correct (pre-)clinical translation, it is of great importance to study the basic mechanisms behind cell therapy in small animal models during this chronic remodeling phase.…”

Clinical management of dilated cardiomyopathy: current knowledge and future perspectives

“…[20] It is however fundamental to remember that longterm studies demonstrates that DCM patients with initial LVRR or even persistent long-term normalization of LVEF induced by medical or resynchronization therapy have a trend toward worsening of LV function or arrhythmic events in the very long term, [21] highlighting the importance of uninterrupted medical therapy and follow-up in those patients.…”