Stem Cell Therapy for Cardiovascular Diseases l黄帝问曰：愿闻十二脏之相使，贵贱何如？岐伯对曰 ：心者，君主之官也，神明出焉。主明则下安，以此 养生则寿，殁世不殆，以为天下则大昌。主不明则十 二官危，使道闭塞而不通，形乃大伤，以此养生则殃 ，以为天下者，其宗大危，戒之戒之。素问灵兰 秘典论 l The life of all animals, from early embryogenesis and throughout adulthood, depends on the second to second uninterrupted function of the heart. Thus, it is not surprising that congenital and acquired diseases of the heart can have catastrophic consequences and that heart disease is the most common cause of adult death worldwide Cardiovascular Diseases (CVDs) A leading health problem, hundred millions of people affected worldwide, 230 million in China and 80 million in US alone CVD types 1. Disease of the vasculature 2. Disease of the myocardium 3. Disease of the electrical circuit 4. Congenital heart disease Heart Development Xin et al., Nat Rev Mol Cell Biol, 2013 Cell Types in the Heart Cardiomyocytes Endothelial cells Smooth muscle cells Fibroblasts Pacemaker cells Purkinjie fibers Epicardium cells Xin et al., Nat Rev Mol Cell Biol, 2013 心脏细胞是否更新？损伤后能否再生？ lHeart was preciously categorized as a post-mitotic organ, unable to undergo substantial renewal during the adult life lTaken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans l1% turning over annually at the age of 25, 0.45% at the age of 75 lFewer than 50% of cardiomyocytes are exchanged during a normal life span Pierro Anversa show the presence in the pathologic adult hearts of active divisions in young myocytes in 1990s Male patients transplanted with female donor hearts- postmortem hearts contain Y-chromosome positive undifferentiated cells expressing Sca-1, c-kit Cardiomyocytes regeneration is extremely low after ischemia Regeneration of Zebra Fish and Neonatal Mouse Heart Xin et al., Nat Rev Mol Cell Biol, 2013 lThe new cardiomyocytes may derive from cardiac progenitor cells or from proliferation of existing cardiomyocytes? lHow do you prove the origin of the new cardiomyocytes? Regeneration of Zebra Fish Heart Jopling et al., Nature, 2010 Regeneration of Neonatal Mouse Heart Porrello et al., Science, 2011 Regeneration of Neonatal Mouse Heart Porrello et al., Science, 2011 Lack of Regeneration of 7-day-old Mouse Heart Porrello et al., Science, 2011 lIschemia/reperfusion injury lCoronary occlusion lDrug-induced cardiomyopathy lHeart failure How to treat? Definition of Stem Cells Self-Renewal Differentiate Generation of contractile myocardium Generation of biological pacemaker and conducting cells Ultimate goal-artificial engineering of a working transplantable heart The goal of stem Cell therapy for Heart Diseases Regenerative Principles For Clinical Cardiac Cell Therapy 1. Stem Cell Isolation and preparation Precise and careful techniques of cell preparation-good manufacturing practice (GMP) conditions Availability of large cell concentrations within the area of interest (e.g. border zone of infarction) Viability needs to reach around 95%. All microbiological tests must prove negative for endogenous (HIV, HBV, HCV) or exogenous contamination. Regenerative Principles For Clinical Cardiac Cell Therapy 2. Ways of stem cell delivery to the heart Intravenous injection is not considered Intracoronary application Intramyocardial stem cell injection during surgery Percutaneous transendocardial injection, facilitated by electromechanical mapping (The NOGA XP Cardiac Navigation System) Regenerative Principles For Clinical Cardiac Cell Therapy 3. Indications and clinical principles for stem cell therapy Best examined indications are previous myocardial infarction with large infarct area, depressed ejection fraction, and heart failure. The age of infarction seems to be irrelevant, since stem cell therapy in old infarcts (older than 8 years) is equally effective Before cell cardiac transplantation, heart failure symptoms, neurohumoral status and the myocardial function and viability should be assessed. Sources of stem cells that have been used for repair of heart disease Therapy using skeletal myoblasts Therapy using skeletal myoblasts Gavira et al., Eur Heart J, 2010 swine coronary occlusion model 3-12 x 106 cells picrosirius red-stain smooth muscle actin The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) Trial: Randomized Placebo- Controlled Study of Myoblast Transplantation Randomized, placebo-controlled, double-blind study included patients with left ventricular (LV) dysfunction (ejection fraction 35%), myocardial infarction, and indication for coronary surgery Ninety-seven patients received myoblasts (400 or 800 million; n=33 and n=34, respectively) or the placebo (n=30) Myoblast injections combined with coronary surgery in patients with depressed LV function failed to improve echocardiographic heart function in 6 month Menasch et al., Circulation, 2008 Therapy using skeletal myoblasts The biggest