Hepatoma-Derived Growth Factor Secreted from Mesenchymal Stem Cells Reduces Myocardial Ischemia-Reperfusion Injury

Abstract

Objectives The present study aimed to explore the major factors that account for the beneficial effects of mesenchymal stem cells (MSCs). Methods Using isobaric tags for relative and absolute quantitation method, hepatoma-derived growth factor (HDGF) was identified as an important factor secreted by MSCs, but not by cardiac fibroblasts (CFs). The protective effects of conditioned medium (CdM) from MSCs or CFs were tested by using either H9C2 cells that were exposed by hypoxia-reoxygenation (H/R) insult or an in vivo mouse model of myocardial ischemia-reperfusion. Results Compared to CF-CdM, MSC-CdM conferred protection against reperfusion injury. CdM obtained from MSCs that were treated with HDGF-targeted shRNA failed to offer any protection in vitro. In addition, administration of recombinant HDGF alone recapitulated the beneficial effects of MSC-CdM, which was associated with increased protein kinase C epsilon (PKCε) phosphorylation, enhanced mitochondria aldehyde dehydrogenase family 2 activity, and decreased 4-hydroxy-2-nonenal accumulation. A significant decrease in infarct size and ameliorated cardiac dysfunction was achieved by administration of HDGF in wild-type mice, which was absent in PKCε dominant negative mice, indicating the essential roles of PKCε in HDGF-mediated protection. Conclusions HDGF secreted from MSCs plays a key role in the protection against reperfusion injury through PKCε activation.

Ischemia Reperfusion Injury Produces, and Ischemic Preconditioning Prevents, Rat Cardiac Fibroblast Differentiation: Role of KATP Channels

“…Vivar et al [38] studied IR injury-induced death and the protective effect of insulin-like growth factor 1 in cultured neonatal rat cardiac fibroblasts. Zhou et al [39,40] established a model of cultured rat neonatal and adult cardiac fibroblasts, in which they have considered the deleterious effects of hypoxia and reperfusion, comparing biochemical and morphological changes in cultured fibroblasts to those of cultured ventricular myocytes [39]. They also found that conditioned media from cultured cardiac fibroblasts subjected to hypoxia and reoxygenation did not protect cardiac myocytes from IR damage, while factors from other non-myocytes of mesenchymal origin did [40]; however, these authors did not consider IR injury beyond changes associated with fibroblast death, or IPC, in their model.…”

“…Zhou et al [39,40] established a model of cultured rat neonatal and adult cardiac fibroblasts, in which they have considered the deleterious effects of hypoxia and reperfusion, comparing biochemical and morphological changes in cultured fibroblasts to those of cultured ventricular myocytes [39]. They also found that conditioned media from cultured cardiac fibroblasts subjected to hypoxia and reoxygenation did not protect cardiac myocytes from IR damage, while factors from other non-myocytes of mesenchymal origin did [40]; however, these authors did not consider IR injury beyond changes associated with fibroblast death, or IPC, in their model. Lefort et al [41] reported that cultured human ventricular fibroblasts produced secretomes in response to 5 h of hypoxia and 24 h reoxygenation, which reduced cardiac myocyte death during the hypoxia/ reoxygenation challenge.…”

Circular RNA Involvement in the Protective Effect of Human Umbilical Cord Mesenchymal Stromal Cell-Derived Extracellular Vesicles Against Hypoxia/Reoxygenation Injury in Cardiac Cells

“…So, it is urgent need for finding novel therapeutic strategies. Mesenchymal stromal cell (MSC)-based therapy is a promising approach following I/R injury ( 2 , 3 ). Different mechanisms are associated with this therapy, such as anti-apoptosis, anti-inflammation, and proangiogenesis ( 4 ).…”