Menstrual blood derived mesenchymal cells ameliorate cardiac fibrosis via inhibition of endothelial to mesenchymal transition in myocardial infarction

Zhu

et al. 2014

PLoS ONE

Self Cite

AimsActivation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI), due to interstitial fibrosis. Mesenchymal stem cells (MSCs) have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC). Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis.MethodsCardiac fibroblast (CF) activation was induced by hypoxia (0.5% O2). The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery.ResultsCo-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs.ConclusionOur data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.

Section: Introductionmentioning

confidence: 99%

Hypoxia Preconditioned Mesenchymal Stem Cells Prevent Cardiac Fibroblast Activation and Collagen Production via Leptin

Zhu

et al. 2014

PLoS ONE

Self Cite

“…Moreover, our group and others have reported that MenSCs possess low immunogenicity and can be stably expanded for at least 20 passages without acquiring genetic abnormalities, emphasizing the convenience of their use , , . The therapeutic potential of MenSCs has been demonstrated in several disease models, such as Duchenne muscular dystrophy, stroke, type 1 diabetes, premature ovarian failure, and myocardial infarction , , further supporting that MenSC‐based therapy may have future clinical applications. While the capacity for MenSCs to differentiate into functional hepatocyte‐like cells has been previously described , , little is known about their therapeutic potential in liver fibrosis.…”

Section: Introductionmentioning

confidence: 65%

Human Menstrual Blood-Derived Stem Cells Ameliorate Liver Fibrosis in Mice by Targeting Hepatic Stellate Cells via Paracrine Mediators

Zhang

Stem Cells Translational Medicine

et al. 2016

106

108

Mesenchymal stem cells (MSCs) may have potential applications in regenerative medicine for the treatment of chronic liver diseases (CLDs). Human menstrual blood is a novel source of MSCs, termed menstrual blood‐derived stem cells (MenSCs). Compared with bone marrow MSCs, MenSCs exhibit a higher proliferation rate and they can be obtained through a simple, safe, painless procedure without ethical concerns. Although the therapeutic efficacy of MenSCs has been explored in some diseases, their effects on liver fibrosis are still unclear. In the present study, we investigated the therapeutic effects of MenSC transplantation in a carbon tetrachloride‐induced mouse model of liver fibrosis. These results revealed that MenSCs markedly improved liver function, attenuated collagen deposition, and inhibited activated hepatic stellate cells up to 2 weeks after transplantation. Moreover, tracking of green fluorescent protein‐expressing MenSCs demonstrated that transplanted cells migrated to the sites of injury, but few differentiated into functional hepatocyte‐like cells. Transwell coculturing experiments also showed that MenSCs suppressed proliferation of LX‐2 cells (an immortalized hepatic stellate cell line) through secretion of monocyte chemoattractant protein‐1, interleukin‐6, hepatocyte growth factor, growth‐related oncogene, interleukin‐8, and osteoprotegerin. Collectively, our results provided preliminary evidence for the antifibrotic capacity of MenSCs in liver fibrosis and suggested that these cells may be an alternative therapeutic approach for the treatment of CLDs. Stem Cells Translational Medicine 2017;6:272–284

“…16,58,59 Another mechanism that may influence the expression of SM22ɑ is an epigenetic modification, for instance, the trimethylation of histone three (H3K27me3) by enhancer of zeste homolog 2 (EZH2) 30 Previously, mesenchymal cells derived from menstrual blood (MMC) were shown to ameliorate cardiac fibrosis via inhibition of EndMT in myocardial infarction. 60 The authors showed that the total number of cells co-expressing CD31 and ɑSMA in the infarcted heart was reduced from 30% in the control group to 20% in the group treated with MMC. In our in vitro study, we also showed that the inhibition of EndMT occurred in a limited manner, corroborating the findings of the in vivo study, which showed the complete blockage of the EndMT process could not be achieved in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, mesenchymal cells derived from menstrual blood (MMC) were shown to ameliorate cardiac fibrosis via inhibition of EndMT in myocardial infarction . The authors showed that the total number of cells co‐expressing CD31 and ɑSMA in the infarcted heart was reduced from 30% in the control group to 20% in the group treated with MMC.…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue–derived stromal cells’ conditioned medium modulates endothelial‐mesenchymal transition induced by IL‐1β/TGF‐β2 but does not restore endothelial function

Liguori

Moreira

et al. 2019

Cell Proliferation

Objectives Endothelial cells undergo TGF‐β–driven endothelial‐mesenchymal transition (EndMT), representing up to 25% of cardiac myofibroblasts in ischaemic hearts. Previous research showed that conditioned medium of adipose tissue–derived stromal cells (ASC‐CMed) blocks the activation of fibroblasts into fibrotic myofibroblasts. We tested the hypothesis that ASC‐CMed abrogates EndMT and prevents the formation of adverse myofibroblasts. Materials and methods Human umbilical vein endothelial cells (HUVEC) were treated with IL‐1β and TGF‐β2 to induce EndMT, and the influence of ASC‐CMed was assessed. As controls, non‐treated HUVEC or HUVEC treated only with IL‐1β in the absence or presence of ASC‐CMed were used. Gene expression of inflammatory, endothelial, mesenchymal and extracellular matrix markers, transcription factors and cell receptors was analysed by RT‐qPCR. The protein expression of endothelial and mesenchymal markers was evaluated by immunofluorescence microscopy and immunoblotting. Endothelial cell function was measured by sprouting assay. Results IL‐1β/TGF‐β2 treatment induced EndMT, as evidenced by the change in HUVEC morphology and an increase in mesenchymal markers. ASC‐CMed blocked the EndMT‐related fibrotic processes, as observed by reduced expression of mesenchymal markers TAGLN (P = 0.0008) and CNN1 (P = 0.0573), as well as SM22α (P = 0.0501). The angiogenesis potential was impaired in HUVEC undergoing EndMT and could not be restored by ASC‐CMed. Conclusions We demonstrated that ASC‐CMed reduces IL‐1β/TGF‐β2‐induced EndMT as observed by the loss of mesenchymal markers. The present study supports the anti‐fibrotic effects of ASC‐CMed through the modulation of the EndMT process.