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Stem cell-derived exosomes as a therapeutic tool for cardiovascular disease

World Journal of Stem Cells 2016年第9期8卷 297-305页

作者： Etsu Suzuki Daishi Fujita Masao Takahashi shigeyoshi oba Hiroaki Nishimatsu Institute of Medical Science St. Marianna University School of Medicine Department of Internal Medicine Faculty of Medicine University of Tokyo Department of Urology Faculty of MedicineUniversity of Tokyo

Mesenchymal stem cells(MSCs) have been used to treat patients suffering from acute myocardial infarction(AMI) and subsequent heart failure. Although it was originally assumed that MSCs differentiated into heart cells such as cardiomyocytes, recent evidence suggests that the differentiation capacity of MSCs is minimal and that injected MSCs restore cardiac function via the secretion of paracrine factors. MSCs secrete paracrine factors in not only naked forms but also membrane vesicles including exosomes containing bioactive substances such as proteins, messenger RNAs, and microR NAs. Although the details remain unclear, these bioactive molecules are selectively sorted in exosomes that are then released from donor cells in a regulated manner. Furthermore, exosomes are specifically internalized by recipient cells via ligand-receptor interactions. Thus, exosomes are promising natural vehicles that stably and specifically transport bioactive molecules to recipient cells. Indeed, stem cell-derived exosomes have been successfully used to treat cardiovascular disease(CVD), such as AMI, stroke, and pulmonary hypertension, in animal models, and their efficacy has been demonstrated. Therefore, exosome administration may be a promising strategy for the treatment of CVD. Furthermore, modifications of exosomal contents may enhance their therapeutic effects. Future clinical studies are required to confirm the efficacy of exosome treatment for CVD.

关键词： Exosomes Messenger RNA Cardiovascular disease Mesenchymal stem cells Stem cells MicroRNA

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Adult stem cells as a tool for kidney regeneration

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World Journal of Nephrology 2016年第1期5卷 43-52页

作者： Etsu Suzuki Daishi Fujita Masao Takahashi shigeyoshi oba Hiroaki Nishimatsu Institute of Medical Science St. Marianna Univer- sity School of Medicine Department of Internal Medicine Faculty of Medicine University of Tokyo Department of Urology Faculty of Medicine University of Tokyo

Kidney regeneration is a challenging but promisingstrategy aimed at reducing the progression to end-stagerenal disease （ESRD） and improving the quality of life of patients with ESRD. Adult stem cells are multipotent stem cells that reside in various tissues, such as bone marrow and adipose tissue. Although intensive studies to isolate kidney stem/progenitor cells from the adult kidney have been performed, it remains controversial whether stem/progenitor cells actually exist in the mammalian adult kidney. The effcacy of mesenchymal stem cells （MSCs） in the recovery of kidney function has been demonstrated in animal nephropathy models, such as acute tubular injury, glomerulonephritis, renal artery stenosis, and remnant kidney. However, their benefcial effects seem to be mediated largely via their paracrine effects rather than their direct differentiation into renal parenchymal cells. MSCs not only secrete bioactive molecules directly into the circulation, but they also release various molecules, such as proteins, mRNA, and microRNA, in membrane-covered vesicles. A detailed analysis of these molecules and an exploration of the optimal combination of these molecules will enable the treatment of patients with kidney disease without using stem cells. Another option for the treatment of patients with kidney disease using adult somatic cells is a direct/indirect reprogramming of adult somatic cells into kidney stem/progenitor cells. Although many hurdles still need to be overcome, this strategy will enable bona fde kidney regeneration rather than kidney repair using remnant renal parenchymal cells.

关键词： Adult stem cells Direct reprogramming Extracellular vesicles Mesenchymal stem cells Paracrine factors Indirect reprogramming

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Chronic kidney disease and erectile dysfunction

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World Journal of Nephrology 2014年第4期3卷 220-229页

作者： Etsu Suzuki Hiroaki Nishimatsu shigeyoshi oba Masao Takahashi Yukio Homma Institute of Medical Science St.Marianna University School of Medicine The Department of Urology Faculty of MedicineUniversity of Tokyo The Department of Internal Medicine Faculty of MedicineUniversity of Tokyo

Erectile dysfunction(ED) is a common condition among male chronic kidney disease(CKD) *** prevalence is estimated to be approximately 80% among these *** has been well established that the production of nitric oxide from the cavernous nerve and vascular endothelium and the subsequent production of cyclic GMP are critically important in initiating and maintaining *** affecting these pathways can induce *** etiology of ED in CKD patients is *** including abnormalities in gonadal-pituitary system,disturbance in autonomic nervous system,endothelial dysfunction,anemia(and erythropoietin deficiency),secondary hyperparathyroidism,drugs,zinc deficiency,and psychological problems are implicated in the occurrence of *** improvement of general conditions is the first step of *** dialysis and adequate nutritional intake are *** addition,control of anemia and secondary hyperparathyroidism is *** of drugs that potentially affect erectile function may be ***,zinc supplementation may be necessary whenzinc deficiency is *** type 5 inhibitors(PDE5Is) are commonly used for treating ED in CKD patients,and their efficacy was confirmed by many *** replacement therapy in addition to PDE5 Is may be useful,particularly for CKD patients with *** transplantation may restore erectile *** is an early marker of cardiovascular disease(CVD),which it frequently precedes; therefore,it is crucial to examine the presence of ED in CKD patients not only for the improvement of the quality of life but also for the prevention of CVD attack.

关键词： Erectile dysfunction Chronic kidney disease Nitric oxide Phosphodiesterase type 5 Testosterone

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Adipose tissue-derived stem cells as a therapeutic tool for cardiovascular disease

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World Journal of Cardiology 2015年第8期7卷 454-465页

作者： Etsu Suzuki Daishi Fujita Masao Takahashi shigeyoshi oba Hiroaki Nishimatsu Institute of Medical Science St. Marianna University School of Medicine the Department of Internal Medicine Faculty of Medicine University of Tokyo the Department of Urology Faculty of Medicine University of Tokyo

Adipose tissue-deried stem cells( ADSCs) are adult stem cells that can be easily harvested from subcutaneous adipose tissue. Many studies have demonstrated that ADSCs differentiate into vascular endothelial cells(VECs), vascular smooth muscle cells(VSMCs), and cardiomyocytes in vitro and in vivo. However, ADSCs may fuse with tissue-resident cells and obtain the corresponding characteristics of those cells. If fusion occurs, ADSCs may express markers of VECs, VSMCs, and cardiomyocytes without direct differentiation into these cell types. ADSCs also produce a variety of paracrine factors such as vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1 that have proangiogenic and/or antiapoptotic activities. Thus, ADSCs have the potential to regenerate the cardiovascular system via direct differentiation into VECs, VSMCs, and cardiomyocytes, fusion with tissueresident cells, and the production of paracrine factors. Numerous animal studies have demonstrated the efficacy of ADSC implantation in the treatment of acute myocardial infarction(AMI), ischemic cardiomyopathy(ICM), dilated cardiomyopathy, hindlimb ischemia, and stroke. Clinical studies regarding the use of autologous ADSCs for treating patients with AMI and ICM have recently been initiated. ADSC implantation has been reported as safe and effective so far. Therefore, ADSCs appear to be useful for the treatment of cardiovascular disease. However, the tumorigenic potential of ADSCs requires careful evaluation before their safe clinical application.

关键词： Adipose tissue-derived stem cells Cardio-vascular disease Acute myocardial infarction Ischemic cardiomyopathy Hindlimb ischemia Stroke

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