3D combinatorial microenvironments for effective cell based therapy

用于有效细胞治疗的 3D 组合微环境

• 批准号: 8111958
• 负责人: Ali Khademhosseini
• 金额: $ 63.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111958
• 关键词: Abbreviations; Adult; Area; Biocompatible Materials; Biological Assay; Biology; Bioluminescence; Biomedical Engineering; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Survival; Cell Therapy; Cell physiology; Cells; Complex; Data; Developed Countries; Development; Differential Scanning Calorimetry; Disease Progression; Echocardiography; Elasticity; Encapsulated; Engineering; Engraftment; Environment; Esters; Ethylene Glycols; Extracellular Matrix; Failure; Fluorescein; Fluorescein-5-isothiocyanate; GAG Gene; Glycosaminoglycans; Goals; Healthcare Systems; Heart; Heart failure; Hyaluronic Acid; Hypoxia; Image; Immunohistochemistry; Implant; In Vitro; Incidence; Infarction; Inflammation; Intervention; Isothiocyanates; Laboratories; Magnetic Resonance Imaging; Mammals; Mechanics; Medical; Methodology; Molecular Biology; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Oxidative Stress; Patients; Phosphate Buffer; Physiology; Play; Polyethylene Glycols; Population; Prevalence; Progenitor Cell Engraftment; Property; Regulation; Research Personnel; Role; Saline; Science; Side; Siloxanes; Skeletal Myoblasts; Stem cells; Stress; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Work; attenuation; carboxyfluorescein; cell capsule; cell type; combinatorial; design; ethylene glycol; functional loss; implantation; improved; in vivo; injured; interest; molecular imaging; mortality; mouse model; nanoindentation; outcome forecast; public health relevance; repaired; stem; stem cell biology; stem cell niche

DESCRIPTION (provided by applicant): Heart failure is the only cardiovascular disease in which prevalence and incidence continue to rise, becoming a tremendous burden for both patients and the healthcare system. The current therapy for heart failure has been focused on the attenuation of the progression of the disease by targeting the neurohumoral factors involved. While successfully improving the prognosis, the morbidity and mortality remains high. Because the loss of functional cardiac muscle cells contributes significantly to the development and progression of heart failure, therapeutic interventions targeted at the regeneration of lost cardiac muscle cells retain enormous medical promise. Towards this goal, cell-based therapy for cardiac regeneration employing various cell types, ranging from skeletal myoblasts to bone marrow derived stem cells to endogenous cardiac stem/progenitor cells, has sparked tremendous interest in recent years. To date, however, true cardiac regeneration has not been achieved, owing largely to the significant loss of cells at the time of implantation and the inability of surviving cells to differentiate into desired cell types in a hostile and diseased myocardium. Maximizing cell engraftment, survival, and differentiation, therefore, remains the greatest hurdle towards therapeutic cardiac regeneration. It is suggested that the impaired survival of implanted cells can be attributed to failure of establishment of contact with the surrounding extracellular matrix (ECM) network in the local microenvironment or niche. Therefore, we hypothesize that establishing contact between implanted stem cells and ECM in a 3D format to mimic a nurturing cellular niche will not only significantly improve engraftment, but also promote functional differentiation. Herein, we aim to employ a system developed using combinatorial approaches to systematically manipulate the local microenvironment encapsulating implanted stem cells, with a goal towards optimizing a transient cellular niche to promote differentiation, to protect stem cells and to augment engraftment during and following implantation. Achieving true cardiac regeneration is a complex and over-arcing goal that any single laboratory would not be able to tackle alone. Therefore, we have assembled a team of investigators and designed an integrated proposal taking advantage of the diverse, yet complementary, expertise from stem cell biology, myocardial biology and physiology, biomaterial science, bioengineering to molecular imaging. Our investigator team has a longstanding and productive track record and will work together to achieve the ultimate goal of therapeutic cardiac regeneration by maximizing stem/progenitor cells engraftment, survival, and differentiation. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the single greatest cause of death in developed countries, claiming more lives in the US than the four next leading causes combined. Among cardiovascular disease, the incidence of heart failure continues to rise at a staggering rate. The loss of functional cardiac cells is essential to the development and progression of heart failure. Medical interventions targeted at the repair and/or regeneration of lost cardiac cells, therefore, hold tremendous promise. Towards this goal, cell-based therapy for cardiac regeneration has sparked tremendous interest in recent years. To date, however, true cardiac regeneration has not been achieved, owing largely to the significant loss of cells at the time of implantation and the inability of surviving cells to differentiate into desired cell types in a hostile and diseased microenvironment. The major goal of our proposal is to maximize cell engraftment, survival, and differentiation. The data obtained from our proposal will contribute significantly towards achieving an ultimate goal of therapeutic cardiac regeneration.

描述（由申请人提供）：心力衰竭是唯一的心血管疾病，其中患病率和发病率继续升高，成为患者和医疗保健系统的巨大负担。当前的心力衰竭疗法通过靶向涉及的神经肿瘤因素，将重点放在疾病进展的衰减上。尽管成功改善了预后，但发病率和死亡率仍然很高。由于功能性心肌细胞的丧失对心力衰竭的发展和进展产生了重大贡献，因此针对丧失心脏肌肉细胞再生的治疗干预措施保持了巨大的医疗承诺。为了实现这一目标，采用各种细胞类型的心脏再生的基于细胞的疗法，范围从骨骼成肌细胞到骨髓衍生的干细胞再到内源性心脏干/祖细胞，在近年来引起了极大的兴趣。然而，迄今为止，尚未实现真正的心脏再生，这在很大程度上是由于植入时的明显损失，并且无法在敌对和患病的心肌中将幸存的细胞分化为所需的细胞类型。因此，最大化细胞植入，生存和分化仍然是朝着治疗性心脏再生的最大障碍。建议植入细胞的存活受损可能归因于在局部微环境或利基市场中与周围细胞外基质（ECM）网络建立接触的失败。因此，我们假设以3D格式建立植入的干细胞与ECM之间的接触以模仿养育细胞属裂市场不仅可以显着改善植入植物，还可以促进功能分化。本文中，我们旨在采用一种使用组合方法开发的系统，以系统地操纵包裹植入的干细胞的局部微环境，目的是优化瞬时细胞壁细胞利基市场以促进分化，保护干细胞并在植入期间和增强植入期间增强植入。 实现真正的心脏再生是一个复杂且过高的目标，任何一个实验室都无法单独解决。因此，我们组建了一个研究人员团队，并设计了一项综合建议，利用了干细胞生物学，心肌生物学和生理学，生物材料科学，生物工程的分子成像的多样化但互补的专业知识。我们的研究人员团队具有长期且富有成效的记录，并将通过最大化茎/祖细胞植入，生存和差异化来共同实现心脏再生的最终目标。 公共卫生相关性：在发达国家，心血管疾病仍然是最大的死亡原因，在美国，其生命远远超过了下一个主要原因。在心血管疾病中，心力衰竭的发生率继续以惊人的速度上升。功能性心脏细胞的丧失对于心力衰竭的发展和发展至关重要。因此，针对丧失心脏细胞的修复和/或再生的医疗干预措施具有巨大的希望。为了实现这一目标，基于细胞的心脏再生疗法在近年来引起了极大的兴趣。然而，迄今为止，尚未实现真正的心脏再生，这主要是由于植入时明显的细胞损失，而幸存的细胞无法在敌对和患病的微环境中分化为所需的细胞类型。我们建议的主要目标是最大化细胞植入，生存和分化。从我们的提案中获得的数据将有助于实现治疗性心脏再生的最终目标。