Stem cell therapy for acute myocardial infarction: MSCs and iPSCs 干细胞治疗急性心肌梗死：MSC 和 iPSC
Diana Clavellina ^(1){ }^{1}, Wayne Balkan ^(1,2){ }^{1,2}, Joshua M Hare ^(1,2,**){ }^{1,2, *} 戴安娜·克拉维利娜 ^(1){ }^{1} ， 韦恩·巴尔干 ^(1,2){ }^{1,2} ， 约书亚·海尔 ^(1,2,**){ }^{1,2, *}^(1){ }^{1} Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA. ^(1){ }^{1} 迈阿密大学米勒医学院跨学科干细胞研究所，美国佛罗里达州迈阿密。2Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. 2迈阿密大学米勒医学院医学系，美国佛罗里达州迈阿密。
Abstract摘要 摘要摘要
Introduction: Acute myocardial infarction (AMI) remains a leading cause of death in the United States. The limited regenerative capacity of cardiomyocytes and the restricted contractility of scar tissue after AMI are not addressed by current pharmacologic interventions. Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach due to their low antigenicity, ease of harvesting, and efficacy and safety in preclinical and clinical studies, despite their low survival and engraftment rates. Other stem cell types, such as induced pluripotent stem cells also show promise and optimizing cardiac repair requires integrating these emerging technologies and strategies. 简介：急性心肌梗死 （AMI） 仍然是美国的主要死亡原因。目前的药物干预并未解决心肌细胞再生能力有限和 AMI 后瘢痕组织收缩力受限的问题。间充质干细胞/基质细胞 （MSCs） 因其抗原性低、易于收获以及临床前和临床研究中的有效性和安全性而成为一种很有前途的治疗方法，尽管它们的存活率和植入率较低。其他干细胞类型，如诱导多能干细胞，也显示出其优势，优化心脏修复需要整合这些新兴技术和策略。
Areas covered: This review offers insights into advancing cell-based therapies for AMI, emphasizing meticulously planned trials with a standardized definition of AMI, for a bench-tobedside approach. We critically evaluate fundamental studies and clinical trials to provide a comprehensive overview of the advances, limitations and prospects for stem cell therapy in AMI. 涵盖的领域：本综述提供了对推进基于细胞的 AMI 疗法的见解，强调精心策划的试验，具有 AMI 的标准化定义，用于从实验室到床旁的方法。我们批判性地评估基础研究和临床试验，以全面概述 AMI 中干细胞治疗的进展、局限性和前景。
Expert opinion: MSCs show undeniable promise for treating AMI, but addressing their low survival and engraftment rates is crucial for clinical success. Integrating emerging technologies and well-designed trials will harness MSC therapy’s full potential in AMI management. Collaborative efforts are vital to developing effective stem cell therapies for AMI patients. 专家意见： MSC 在治疗 AMI 方面显示出不可否认的前景，但解决其低生存率和植入率对于临床成功至关重要。整合新兴技术和精心设计的试验将充分利用 MSC 疗法在 AMI 管理中的潜力。合作努力对于为 AMI 患者开发有效的干细胞疗法至关重要。
Acute myocardial infarction (AMI) prominently figures as one of the principal drivers of death in the United States. Despite efforts involving interventional and pharmacological strategies, AMI still accounts for more than one hundred thousand deaths annually [1]. Every 40 seconds on average, an American will suffer a myocardial infarction (MI) [1]. The resulting heart failure accounts for almost 30%30 \% of the mortality in patients aged 65 and older suffering from this condition [1]. 急性心肌梗死 （AMI） 是美国死亡的主要驱动因素之一。尽管采取了干预和药物策略方面的努力，但 AMI 每年仍导致超过 10 万人死亡 [1]。平均每 40 秒，就有一名美国人患上心肌梗死 （MI） [1]。由此产生的心力衰竭几乎 30%30 \% 占 65 岁及以上患有这种疾病的患者的死亡率 [1]。
Thus, there is an unmet and urgent need for novel strategies to contain the injury to the cardiac cells following an AMI. Current management guidelines aim to contain progressive cardiac necrosis [2,3]. In cases of extensive damage, when the severity reaches a certain threshold, the only option remaining is a heart transplant, which holds significant challenges, such as host-recipient immune compatibility and the short supply of heart donors [4]. And even if reperfusion is achieved in a timely manner, myocardial damage and dysfunction of the microcirculation are still unavoidable complications [5]. Thus, strategies to repair/ regenerate the myocardium and improve the surrounding ischemic environment are vital for achieving optimal cardiac functional recovery following an AMI. Stem cells have been extensively explored in rescuing the damaged micro-vessels and reinforcing myocardial healing mechanisms due to their limited immunogenic properties and differentiation. 因此，存在未满足的迫切需求，需要新的策略来控制 AMI 后对心肌细胞的损伤。目前的管理指南旨在控制进行性心脏坏死 [2,3]。在大面积损伤的情况下，当严重程度达到一定阈值时，剩下的唯一选择是心脏移植，这存在重大挑战，例如宿主-受体免疫相容性和心脏供体供应短缺 [4]。即使及时实现再灌注，心肌损伤和微循环功能障碍仍然是不可避免的并发症 [5]。因此，修复/再生心肌和改善周围缺血环境的策略对于在 AMI 后实现最佳心脏功能恢复至关重要。由于免疫原性和分化有限，干细胞在挽救受损的微血管和加强心肌愈合机制方面已被广泛探索。
Mesenchymal stem/stromal cells (MSCs) show anti-apoptotic, vasculogenic, and antiinflammatory benefits and improve myocardial structure and function [6]. Despite findings on the safety and positive impact of stem cells in improving left ventricular ejection fraction (LVEF) [7], challenges arise from the limited survival and inadequate engraftment of the transplanted cells. induced pluripotent stem cells (iPSCs) are novel candidates with encouraging prospects, iPSCs represent great potential, but their long-term expansion and manufacturing costs hamper their clinical translation. This review will center on the pivotal mechanisms employed by MSCs in cardiac repair and provide an overview of recent investigations into cell therapy as a potential treatment approach for AMI. 间充质干细胞/基质细胞 （MSCs） 具有抗凋亡、血管生成和抗炎作用，并改善心肌结构和功能 [6]。尽管发现了干细胞在改善左心室射血分数 （LVEF） 方面的安全性和积极影响 [7]，但移植细胞的生存率有限和植入不充分带来了挑战。诱导多能干细胞 （iPSC） 是前景令人鼓舞的新型候选药物，iPSC 具有巨大的潜力，但它们的长期扩增和制造成本阻碍了其临床转化。本综述将集中在 MSCs 在心脏修复中采用的关键机制，并概述最近对细胞疗法作为 AMI 潜在治疗方法的研究。
2. Acute myocardial infarction: a loosely defined concept 2. 急性心肌梗死：一个定义松散的概念
The conventional definition of MI encompasses identification of acute myocardial injury, typically characterized by atypical heart biomarkers, and evidence of acute myocardial ischemia (i.e., ischemic chest symptoms and changes in electrocardiography pattern) [8]. An MI is triggered by the erosion or rupture of an underlying atheroma, resulting in thrombosis, and reduced coronary lumen diameter [9]. The ischemic myocardium activates molecular and cellular signaling, intense inflammatory responses, dysregulation of angiogenic pathways and cardiomyocyte necrosis in the hypoperfused area. The subsequent healing processes aims to resolve the inflammation and re-establish the integrity of the injured area [10] by developing a collagen scar to replace the necrotic tissue. This healing process ultimately leads to adverse structural and mechanical changes known as ventricular remodeling to adapt to the changes in the myocardial mechanical strength of the left ventricle (LV). Cardiac remodeling yields thinned LV wall with less muscle mass, dilated ventricle and compromised cardiac contractility [11]. 心肌梗死的常规定义包括识别急性心肌损伤（通常以非典型心脏生物标志物为特征）和急性心肌缺血证据（即缺血性胸部症状和心电图模式改变）[8]。心肌梗死是由潜在动脉粥样硬化的糜烂或破裂引发的，导致血栓形成和冠状动脉管腔直径减小[9]。缺血性心肌激活分子和细胞信号传导、强烈的炎症反应、血管生成途径失调和低灌注区域的心肌细胞坏死。随后的愈合过程旨在通过形成胶原疤痕来替换坏死组织，从而解决炎症并重新建立受伤区域的完整性 [10]。这种愈合过程最终导致不利的结构和机械变化，称为心室重塑，以适应左心室 （LV） 心肌机械强度的变化。心脏重塑导致左心室壁变薄，肌肉质量减少，心室扩张，心脏收缩力受损 [11]。
A myocardial injury is considered acute only when accompanied by changes in bio-markers of myocardial necrosis values, namely cardiac troponin I (cTnI) and cardiac troponin T (cTnT) [8]. After an MI, cardiac troponins reach a maximum concentration in the bloodstream at 10 to 20 hours after onset of acute ischemia in patients receiving reperfusion interventions or at 24 to 50 hours in non-treated patients. The concentrations of cTnI and cTnT directly correlate with the injury area in those patients without reperfusion therapy [12]. 只有当伴有心肌坏死值的生物标志物发生变化时，即心肌肌钙蛋白 I （cTnI） 和心肌肌钙蛋白 T （cTnT） [8] 才被认为是急性心肌损伤。心肌肌钙蛋白在 MI 后，接受再灌注干预的患者在急性缺血发作后 10 至 20 小时或未治疗的患者在 24 至 50 小时达到血流中的最大浓度。对于未接受再灌注治疗的患者，cTnI 和 cTnT 的浓度与损伤区域直接相关 [12]。
Criteria for diagnosing MI also include alterations in the ST segment observed by electrocardiography. Broadly, MI can be subclassified into two main subtypes: ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) [13]. MI classification is also based on histologic observation of characteristic cells at each phase of the repair process. The entire process of achieving a healed phase takes ∼5\sim 5 to 6 weeks [14]. A less precise definition categorizes MI based on distinct phases of histologic features, namely acute (occurring within 6 hours to 7 days), healing (occurring between 7 and 28 days), and healed (occurring 29 days or more) from the onset of the initial injury [8]. Based on AMI interventional strategies, patients seen within 12 hours or between 12 to 48 after symptom onset are early or late presenters, respectively. According to the International Statistical Classification of Diseases and Related Health Problems 10th Revision, acute myocardial infarction is classified when it occurs within a period of 4 weeks from the onset [15]. The clinical and electrocardiographic timing of acute infarction onset may not necessarily match with histologic characteristics. Thus, the definition of AMI varies depending on the study approach. 诊断 MI 的标准还包括心电图观察到的 ST 段改变。从广义上讲，心肌梗死可分为2大亚型：ST段抬高型心肌梗死（ST-elevation myocardial infarction， STEMI）和非ST段抬高型心肌梗死（non-ST-elevation myocardial infarction， NSTEMI）[13]。MI 分类也基于对修复过程每个阶段特征细胞的组织学观察。达到愈合阶段的整个过程需要 ∼5\sim 5 6 周 [14]。MI根据组织学特征的不同阶段进行不太精确的定义，即急性（发生在6小时至7日内）、愈合（发生在7-28日之间）和愈合（发生在29日或更长时间）[8]。根据 AMI 介入策略，症状出现后 12 小时内或 12 至 48 小时内就诊的患者分别为早期或晚期表现者。根据《疾病和相关健康问题国际统计分类》（International Statistical Classification of Diseases and Related Health Problems）第10版，急性心肌梗死在发病后4周内发生时被归类[15]。急性梗死发作的临床和心电图时间不一定与组织学特征相匹配。因此，AMI 的定义因研究方法而异。
The inherent ability of the human heart to self-renew is limited, and the rate of cardiomyocyte turnover decreases progressively through the lifespan. Only ∼60%\sim 60 \% of the cardiomyocytes present at birth will survive to the age of 50 [16]. The search for new approaches to reverse the loss of cardiac tissue has motivated the development of cardiovascular regenerative medicine (CRM) [10]. CRM represents a cutting-edge approach within the medical field, aiming to repair damaged heart tissue through strategies such as tissue engineering, cell and gene therapy. The Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes is an international consortium dedicated to advancing CRM by fostering global collaboration, setting unified standards, and translating scientific research into effective clinical applications for treating cardiovascular diseases [17]. 人体心脏的内在自我更新能力是有限的，心肌细胞的周转率在一生中逐渐降低。只有 ∼60%\sim 60 \% 出生时存在的心肌细胞才能存活到 50 岁 [16]。寻找逆转心脏组织损失的新方法推动了心血管再生医学 （CRM） 的发展 [10]。CRM 代表了医学领域的一种前沿方法，旨在通过组织工程、细胞和基因治疗等策略修复受损的心脏组织。心血管综合征再生疗法跨国联盟是一个国际联盟，致力于通过促进全球合作、制定统一标准以及将科学研究转化为治疗心血管疾病的有效临床应用来推进 CRM [17]。
3. The search for the best cell 3. 寻找最佳单元格
The search for the optimal cell type in cell-based regenerative medicine for acute MI is a critical area of investigation to identify the cell type that offers the most significant regenerative potential and therapeutic benefits. Numerous cell types have been explored. Each cell type possesses distinct characteristics and mechanisms of action, making it crucial to identify the optimal cell source for effective cardiac repair and regeneration. Cell types used in treating AMI both clinically and pre-clinically include skeletal myoblasts [18], bone marrow mononuclear cells (BMMNCs) [19], cardiac progenitor cells [20,21], cardiospherederived cells [22], MSCs, embryonic stem cells (ESCs) [23], and iPSCs [24]. These studies 在基于细胞的再生医学中寻找急性 MI 的最佳细胞类型是一个关键的研究领域，以确定提供最显着再生潜力和治疗益处的细胞类型。已经探索了多种细胞类型。每种细胞类型都具有不同的特性和作用机制，因此确定有效心脏修复和再生的最佳细胞来源至关重要。临床和临床前用于治疗AMI的细胞类型包括骨骼成肌细胞[18]、骨髓单核细胞（BMMNC）[19]、心脏祖细胞[20,21]、心脏球源性细胞[22]、MSC、胚胎干细胞（ESC）[23]和iPSC[24]。这些研究
*Corresponding author: Joshua M Hare; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136; Telephone: (305) 243-5579; Fax: (305) 243-5584; JHare@med.miami.edu. *通讯作者：Joshua M Hare;迈阿密大学米勒医学院跨学科干细胞研究所， 迈阿密， FL 33136;电话：（305） 243-5579;传真：（305） 243-5584;JHare@med.miami.edu。
Declaration of interest 利益声明
JM Hare reported having a patent for cardiac cell-based therapy. He holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. JM Hare is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron, and holds equity in Longeveron. He is also the co-inventor of intellectual property licensed to Longeveron. Longeveron LLC and Vestion Inc. did not participate in funding this work. JM Hare’s relationships are disclosed to the University of Miami, and a management plan is in place. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. JM Hare 报告称拥有基于心肌细胞的疗法专利。他持有 Vestion Inc. 的股权，并作为顾问、董事会成员和科学顾问委员会成员与 Vestion Inc. 保持着专业关系。JM Hare 是 Longeveron 的首席科学官、有偿顾问和顾问委员会成员，并持有 Longeveron 的股权。他还是授权给 Longeveron 的知识产权的共同发明人。Longeveron LLC 和 Vestion Inc. 没有参与为这项工作提供资金。JM Hare 的关系已向迈阿密大学披露，并制定了管理计划。除已披露的主题或材料外，作者与任何与手稿中讨论的主题或材料有经济利益或财务冲突的组织或实体没有其他相关隶属关系或财务参与。
Reviewer disclosures 审阅者披露
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. 本手稿的同行评审员没有相关的财务或其他关系需要披露。