Toward Regeneration of Whole Bioartificial Human Heart

走向整个生物人工心脏的再生

• 批准号: 8749862
• 负责人: Lei Yang
• 金额: $ 139.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749862
• 关键词: Affect; American; Architecture; Biocompatible Materials; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cells; Complex; Contracts; Endothelial Cells; Engineering; Exhibits; Extracellular Matrix; Future; Heart; Heart Diseases; Heart Transplantation; Heart failure; Human; In Situ; Intervention; Life; Mus; Muscle; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Outcome; Patients; Pharmaceutical Preparations; Preclinical Drug Evaluation; Regenerative Medicine; Resources; Smooth Muscle Myocytes; Solutions; Staging; Stem cells; Structure; Testing; Tissue Engineering; Tissues; United States; biomaterial compatibility; cardiogenesis; heart cell; heart function; heart valve replacement; implantation; induced pluripotent stem cell; novel strategies; progenitor; public health relevance; regenerative; scaffold; treatment strategy

DESCRIPTION (provided by applicant): Heart disease is the leading death cause in the United States. Myocardial infarction (MI) affects over 80 million American people and approximately 5 million Americans are living with heart failure, which increases with an annual rate of about 500,000 new cases. Given the limited regenerative capability of heart, end stage heart failure is irreversible and heart function of MI patients cannot be spontaneously recovered. Heart transplantation is the ultimate treatment strategy for end stage heart failure patients. However, approximately 50,000 people die each year due to the limited availability of donor hearts for transplant. Heart tissue engineering offers the potential of making cardiac tissues ex vivo for future therapy of heart disease, such as for replacement of cardiac valves, myocardium implantation, drug screening, as well as engineering functional whole heart for transplantation. Heart tissue engineering requires a resource of cardiovascular cells and three dimensional (3D) scaffolds. The general strategy of engineering heart tissue is achieved by mixing functional non-human heart cells, such as beating neonatal mouse CMs and vascular cells, with biomaterial matrices. A variety of synthetic and natural derived matrices have been utilized. However, most of the synthetic matrices have biocompatibility problems and do not preserve the same 3D architectures, complex compositions and micro-niches as the extracellular matrix (ECM) in native heart, which functions to support heart formation and maintain heart function. In addition, due to the limited availability of human heart cells, human heart tissue engineering has been largely remained underdeveloped. Recently we developed a novel strategy for rebuilding human heart constructs by recellularizing whole acellular mouse hearts with multipotential cardiovascular progenitors (MCPs) derived from human induced pluripotent stem (iPS) cells. MCPs represent the earliest human heart progenitors in human cardiogenesis. When reseeded into acellular mouse hearts, MCPs in situ differentiated into cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs) with high efficiency, which reconstructed the decellularized mouse hearts. The engineered heart constructs exhibited muscle and vessel-like structures, contracted spontaneously with a rate of 40-50 beats per min, exhibited intracellular Ca2+ transients and responded as expected to various drug interventions. Therefore our study established a novel strategy, which could be used to regenerate personalized human heart tissues as well as whole hearts using patient-specific iPS cells. The central aim of this proposal is to test whether human iPS cell- derived MCPs could be used to repopulate whole acellular human heart scaffolds for rebuilding whole bioartificial human hearts. In addition, we will examine the impact of human heart ECMs on CM commitment from reseeded human MCPs. Outcome of this proposal will be significant for the future translational therapy of human heart disease.

描述（由申请人提供）：心脏病是美国的主要死亡原因。心肌梗塞（MI）影响超过8000万美国人，约有500万美国人患有心力衰竭，每年约为50万例新病例的速度增加。鉴于心脏的再生能力有限，终阶段的心力衰竭是不可逆的，MI患者的心脏功能不能自发恢复。心脏移植是最终阶段心力衰竭患者的最终治疗策略。但是，由于捐助者心脏的移植供应有限，每年约有50,000人死亡。心脏组织工程提供了使心脏组织离体的潜力，以便将来治疗心脏病，例如替代心脏瓣膜，心肌植入，药物筛查以及工程功能性的全心心脏以进行移植。心脏组织工程需要心血管细胞和三维（3D）支架的资源。通过混合功能性非人类心脏细胞（例如将新生小鼠CMS和血管细胞）与生物材料基质混合，可以实现工程心脏组织的一般策略。已经使用了多种合成和自然派生的矩阵。但是，大多数合成矩阵都有生物相容性问题，并且不保留与天然心脏中相同的3D架构，复杂的组成和微型细胞基质（ECM），这起作用可支持心脏形成和维持心脏功能。此外，由于人类心脏细胞的可用性有限，人类心脏组织工程的发展基本不足。最近，我们通过用源自人类诱导的多能茎（IPS）细胞的多重级心血管祖细胞（MCP）来重建整个细胞小鼠心脏，开发了一种新的策略来重建人心脏构建体。 MCP代表了人类心脏病中最早的人类心脏祖细胞。当恢复到细胞小鼠心脏中时，MCP的原位分化为心肌细胞（CMS），平滑肌细胞（SMC）和内皮细胞（ECS），其效率很高，从而重建了脱细胞小鼠心脏。工程的心脏构建体表现出肌肉和血管样结构，自发收缩，每分钟40-50次均为40-50次，表现出细胞内Ca2+瞬变，并按照预期的各种药物干预做出了反应。因此，我们的研究建立了一种新型策略，可用于使用患者特异性IPS细胞再生个性化的人心脏组织以及整个心脏。该提案的核心目的是测试人IPS细胞衍生的MCP是否可用于重建整个细胞人类心脏支架，以重建整个生物人工人工心脏。此外，我们将研究人类心脏ECM对已恢复的人MCP的CM承诺的影响。该提案的结果对于人心脏病的未来翻译疗法将是重要的。