实现人类心肌的再生：干细胞的风雨路

doi:10.3969/j.issn.1674-490X.2015.04.012

摘要/Abstract

摘要： 如何实现人类心肌的再生，科研工作者和临床医生已经为之努力了近一个世纪。1953 年，实施了第一例室间隔缺损修复手术，1967 年第一例心脏移植成功，2002 年骨髓来源的细胞首次移植到心肌内，使心肌的修复取得重大进步。然而慢性心力衰竭仍是世界范围内的难题。为什么实现心肌的再生面临巨大的挑战？要实现心肌的再生还有多远？细胞移植技术近年已取得突飞猛进的进步，许多大型动物实验结果带来了曙光和挑战。将对心肌再生的历史和临床研究进行探讨，对干细胞的实施和目前正在进行的实验进行综述。

关键词: 再生医学, 干细胞, 心肌

Abstract: Regenerating the human heart is a challenge that has engaged researchers and clinicians around the globe for nearly a century. From the repair of the first septal defect in 1953, followed by the first successful heart transplant in 1967, and later to the first infusion of bone marrow-derived cells to the human myocardium in 2002, significant progress has been made in heart repair. However, chronic heart failure remains a leading pathological burden worldwide. Why has regenerating the human heart been such a challenge, and how close are we to achieve clinically relevant regeneration? Exciting progress has been made to establish cell transplantation techniques in recent years, and new preclinical studies in large animal models have shed light on the promises and challenges that lie ahead. In this review, we will discuss the history of cell therapy approaches and provide an overview of clinical trials using cell transplantation for heart regeneration. Focusing on the delivery of human stem cell derived cardiomyocytes, current experimental strategies in the field will be discussed as well as their clinical translation potential.

Key words: regenerative medicine, stem cells, myocardium

瞿海龙，梁璐，边剑飞，张冰. 实现人类心肌的再生：干细胞的风雨路[J]. 医学研究与教育, 2015, 32(4): 50-55.

JU Hailong，LIANG Lu，BIAN Jianfei，ZHANG Bing. The hard road to regenerating the human heart[J]. Medical Reserch and Education, 2015, 32(4): 50-55.

参考文献

[1] GO A S, MOZAFFARIAN D, ROGER V L, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association[J]. Circulation, 2013, 127(1): e6-e245. [2] LOZANO R, NAGHAVI M, FOREMAN K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010[J]. Lancet, 2013, 381(9867): 628. [3] FUTAKUCHI-TSUCHIDA A, MURRY C E. Human myocardial grafts: do they meet all the criteria for true heart regeneration? [J] Future Cardiol, 2013, 9(2): 151-154. [4] STRAUER BE, BREHM M, ZEUS T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans[J]. Circulation, 2002, 106(15): 1913-1918. [5] MALLIARAS K, MARBA / N E. Cardiac cell therapy: where we've been, where we are, and where we should be headed[J]. Br Med Bull, 2011，98(1): 161-185. [6] WOLLERT K C, MEYER G P, LOTZ J. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial[J]. Lancet, 2004, 364(9429): 141-148. [7] MEYER G P, WOLLERT K C, LOTZ J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial[J]. Circulation, 2006, 113(10): 1287-1294. [8] SCHACHINGER V, ERBS S, ELSASSER A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction[J]. N Engl J Med, 2006, 355(12): 1210-1221. [9] LEISTNER D M, FISCHER-RASOKAT U, HONOLD J, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy[J]. Clin Res Cardiol, 2011, 100(10): 925-934. [10] PERIN E C, WILLERSON J T, PEPINE C J, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial[J]. JAMA, 2012 , 307(16): 1717-1726. [11] TRAVERSE J H, HENRY T D, VAUGHAN D E, et al. LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction[J]. Tex Heart Inst J, 2011, 37(4): 412-420. [12] SURDER D, MANKA R, Lo CICERO V, et al. Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function[J]. Circulation, 2013, 127(19): 1968-1979. [13] 瞿海龙, 麻月云, 边剑飞. 干细胞治疗心脏疾患研究进展[J]. 医学研究与教育, 2014, 31(5): 55-58. [14] CHEN S L, FANG W W, YE F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction[J]. Am J Cardiol, 2004, 94(1): 92-95. [15] HELDMAN A W, DIFEDE D L, FISHMAN J E, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial[J]. JAMA , 2014, 311(1): 62-73. [16] HARE J M, FISHMAN J E, GERSTENBLITH G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial[J]. JAMA, 2012, 308(22): 2369-2379. [17] BARTUNEK J, BEHFAR A, DOLATABADI D, et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failure) multicenter randomized trial with lineage-specified biologics[J]. J Am Coll Cardiol, 2013, 61(23): 2329-2338. [18] 瞿海龙, 麻晓静, 张冰, 等. 干细胞在心肌再生中的研究进展[J]. 医学研究与教育, 2011, 28(4): 62-64. [19] LI T S, CHENG K, MALLIARAS K, et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells[J]. J Am Coll Cardiol, 2012 , 59(10): 942-953. [20] BOLLI R, CHUGH A R, D'AMARIO D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial[J]. Lancet, 2011, 378(9806): 1847-1857. [21] MALLIARAS K, MAKKAR R R, SMITH R R, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (Cardiosphere-Derived autologous stem cells to reverse ventricular dysfunction) [J]. J Am Coll Cardiol, 2014, 63(2): 110-122. [22] BURRIDGE P W, KELLER G, GOLD J D, et al. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming[J]. Cell Stem Cell, 2012, 10(1): 16-28. [23] MAHER K O, XU Chunhui. Marching towards regenerative cardiac therapy with human pluripotent stem cells[J]. Discov Med, 2013, 15(85): 349-356. [24] SHIBA Y, FILICE D, FERNANDES S, et al. Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model[J]. J Cardiovasc Pharmacol Ther, 2014, 19(4): 368-381. [25] CHONG J J, YANG X, DON C W, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts[J]. Nature, 2014, 510(7504): 273-277.