Rationale : Autophagy can preserve cell viability under conditions of mild ischemic stress by degrading damaged organelles for ATP production, but under conditions of severe ischemia, it can promote cell death and worsen cardiac performance. Mesenchymal stem cells (MSCs) are cardioprotective when tested in animal models of myocardial infarction, but whether these benefits occur through the regulation of autophagy is unknown. Objective:: To determine whether transplanted MSCs reduce the rate of autophagic degradation (autophagic flux) in infarcted hearts and if so, to characterize the mechanisms involved. Methods and Results:: Treatment with transplanted MSCs improved cardiac function and infarct size while reducing apoptosis and measures of autophagic flux (bafilomycin A1-induced LC3-II [microtubule-associated protein 1 light chain 3] accumulation and autophagosome/autolysosome prevalence) in infarcted mouse hearts. In hypoxia and serum deprivation–cultured neonatal mouse cardiomyocytes, autophagic flux and cell death, as well as p53-Bnip3 (B-cell lymphoma 2–interacting protein 3) signaling, declined when the cells were cultured with MSCs or MSC-secreted exosomes (MSC-exo), but the changes associated with MSC-exo were largely abolished by pretreatment with the exosomal inhibitor GW4869. Furthermore, a mimic of the exosomal oligonucleotide miR-125b reduced, whereas an anti-miR-125b oligonucleotide increased, autophagic flux and cell death, via modulating p53-Bnip3 signaling in hypoxia and serum deprivation–cultured neonatal mouse cardiomyocytes. In the in vivo mouse myocardial infarction model, MSC-exo, but not the exosomes obtained from MSCs pretreated with the anti-miR-125b oligonucleotide (MSC-exo ^{anti-miR-125b} ), recapitulated the same results as the in vitro experiments. Moreover, measurements of infarct size and cardiac function were significantly better in groups that were treated with MSC-exo than the MSC-exo ^{anti-miR-125b} group. Conclusions:: The beneficial effects offered by MSC transplantation after myocardial infarction are at least partially because of improved autophagic flux through excreted exosome containing mainly miR-125b-5p.

Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (Exo^H) are superior to those from normoxia-treated MSCs (Exo^N) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. Exo^H resulted in significantly higher survival, smaller scar size and better cardiac functions recovery. Exo^H conferred increased vascular density, lower cardiomyocytes (CMs) apoptosis, reduced fibrosis and increased recruitment of cardiac progenitor cells in the infarcted heart relative to Exo^N. MicroRNA analysis revealed significantly higher levels of microRNA-210 (miR-210) in Exo^H compared with Exo^N. Transfection of a miR-210 mimic into endothelial cells (ECs) and CMs conferred similar biological effects as Exo^H. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secretion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the beneficial effects of Exo^H. In conclusion, hypoxic culture augments miR-210 and nSMase2 activities in MSCs and their secreted exosomes, and this is responsible at least in part for the enhanced cardioprotective actions of exosomes derived from hypoxia-treated cells.

Insulin resistance and hypertension are considered as prototypical “diseases of civilization” that are manifested in the modern environment as plentiful food and sedentary life. The human propensity for insulin resistance and hypertension is a product, at least in part, of our evolutionary history. Adaptation to ancient lifestyle characterized by a low sodium, low-calorie food supply and physical stress to injury response has driven our evolution to shape and preserve a thrifty genotype, which is favorite with energy-saving and sodium conservation. As our civilization evolved, a sedentary lifestyle and sodium- and energy-rich diet, the thrifty genotype is no longer advantageous, and may be maladaptive to disease phenotype, such as hypertension, obesity and insulin resistance syndrome. This article reviews human evolution and the impact of the modern environment on hypertension and insulin resistance.

Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue. Key recent published literatures and ClinicalTrials.gov. Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases. The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects. Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases. Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future.

Rationale:: Human pluripotent stem cell–derived cardiovascular progenitor cells (hPSC-CVPCs) should be thoroughly investigated in large animal studies before testing in clinical trials. Objective:: The main of this study is to clarify whether hPSC-CVPCs can engraft for long time in the heart of primates after myocardial infarction (MI) and compare the effectiveness and safety of immunosuppression with cyclosporine alone or multiple-drug regimen (MDR) containing cyclosporine, methylprednisolone, and basiliximab in cynomolgus monkeys that had received intramyocardial injections of 1×10 ⁷ EGFP (enhanced green fluorescent protein)-expressing hPSC-CVPCs after MI. A third group of animals received the immunosuppression MDR but without cell therapy after MI (MI+MDR group). Methods and Results:: Measurements of EGFP gene levels and EGFP immunofluorescence staining indicated that the hPSC-CVPC engraftment rate was greater in the MI+MDR+CVPC group than that in the MI+cyclosporine+CVPC group. However, even in the MI+MDR+CVPC group, no transplanted cells could be detected at 140 days after transplantation. Concomitantly, immunofluorescent analysis of CD3, CD4, and CD8 expression indicated that T-lymphocyte infiltration in the CVPC-transplanted hearts was less in the MDR-treated animals than in the cyclosporine-alone–treated animals. The recovery of left ventricular function on day 28 post-MI in the MI+MDR+CVPC group was better than that in the MI+MDR group. Apoptotic cardiac cells were also less common in the MI+MDR+CVPC group than in the MI+MDR group, although both immunosuppression regimens were associated with transient hepatic dysfunction. Conclusions:: This is the largest study of hPSCs in nonhuman primates in cardiovascular field to date (n=32). Compared with cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates; this is associated with less apoptosis of native cardiac cells and better recovery of left ventricular function at 28 days. However, even with MDR, transplanted hPSC-CVPCs do not engraft and do not survive at 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.

Exosomes play a critical role in intercellular communication since they contain signalling molecules and genetic materials. During tumorigenesis, tumour‐derived exosomes have been demonstrated to promote tumour angiogenesis and metastasis. However, how the exosomes facilitate tumour metastasis is not clear. Here we explored the effect of HeLa cell‐derived exosomes (Exo ^HeLa ) on endothelial tight junctions (TJ) and the related mechanisms. After human umbilical vein endothelial cells (HUVEC) were treated with Exo ^HeLa , TJ proteins zonula occludens‐1 (ZO‐1) and Claudin‐5 in HUVEC were significantly reduced as compared with that treated with exosomes from human cervical epithelial cells, while mRNA levels of ZO‐1 and Claudin‐5 remained unchanged. Consequently, permeability of endothelial monolayer was increased after the treatment with Exo ^HeLa . Injection of Exo ^HeLa into mice also increased vascular permeability and tumour metastasis in vivo . Neither knocking down of Dicer nor use of inhibitors of microRNAs targeting at mRNAs of ZO‐1 and Claudin‐5 could block the inhibitory effect of Exo ^HeLa on ZO‐1 and Claudin‐5. The expression of genes involved in endoplasmic reticulum (ER) stress was significantly increased in HUVECs after treated with Exo ^HeLa . Inhibition of ER stress by knocking down protein kinase RNA‐like endoplasmic reticulum kinase prevented the down‐regulation of ZO‐1 and Claudin‐5 by Exo ^HeLa . Our study found that HeLa cell‐derived exosomes promote metastasis by triggering ER stress in endothelial cells and break down endothelial integrity. Such effect of exosomes is microRNA‐independent.