Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium

Abstract

Although paracrine effects of mesenchymal stem cells (MSCs) have been suggested previously, cardioprotection by human MSC secretions has never been demonstrated. Human MSC-conditioned medium (CM) was collected by following a clinically compliant protocol. In a porcine model of ischemia and reperfusion injury, intravenous and intracoronary MSC-CM treatment significantly reduced myocardial nuclear oxidative stress as determined by immunostaining for 8-hydroxy-2'-deoxyguanosine. In addition, expression levels of phospho-SMAD2 and active caspase 3 were diminished following CM treatment, suggesting that TGF-beta signaling and apoptosis were reduced. This was associated with a 60% reduction in infarct size and marked improvement of systolic and diastolic cardiac performance as assessed with echocardiography and pressure volume loops. Fractionation studies revealed that only the fraction of the CM containing products >1000 kDa (100-220 nm) provided cardioprotection in a mouse model of ischemia and reperfusion injury. This indicates that the responsible paracrine factor of human MSCs is likely a large complex rather than a single small molecule. These data identify human MSC-CM as a promising therapeutic option to reduce myocardial infarct size in patients with acute MI and suggest that the use of stem cell secretions could extend the applicability of stem cells for therapeutic purposes.

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

“…The most important components within the secretome are the exosomes, which transfer bioactive molecules (such as mRNAs and microRNAs) between cells. 27,28 The exchange of genetic information together with microRNAs leads to reprogramming of recipient cells, allowing them to regenerate damaged tissue. 29,30 In our preclinical studies where human melanoma cells, 9 prostate cancer cells 10 were implanted subcutaneously to immunocompromised nude mice, a significant tumor growth inhibition was observed when suicide gene-engineered MSCs were intravenously injected.…”

Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles

“…Thus, it was considered that comparable as in acute GvHD paracrine rather than cellular effects mediate the improvement of cardiac functions following myocardial infarction. Indeed, different labs recovered cardioprotective activities in MSC conditioned media (57)(58)(59). Upon searching for the cardioprotective factors secreted by MSCs, Lee and colleagues identified the anti-inflammatory protein TNF-α-induced protein 6 (TSG-6).…”

Cardiovascular Diseases: Recent Developments in Regenerative Medicine

“…These exosomes induce angiogenesis in endothelial cells by direct transfer of mRNA. Timmers L et al [33] demonstrated that media conditioned with hMSC reduce infarct size by 59% in animal model of myocardial ischemia [33].…”