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: 8000572
• 负责人: Ali Khademhosseini
• 金额: $ 63.78万
• 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/8000572
• 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; Fluoresceins; GAG Gene; Glycosaminoglycans; Goals; Healthcare Systems; Heart; Heart failure; Hyaluronic Acid; Hypoxia; Image; Immunohistochemistry; Implant; In Vitro; Incidence; Infarction; Inflammation; Intervention; Isothiocyanates; Laboratories; Life; Magnetic Resonance Imaging; Mammals; Mechanics; Medical; Methodology; Molecular Biology; Morbidity - disease rate; Mus; Muscle Rigidity; 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）：心力衰竭是唯一一种患病率和发病率持续上升的心血管疾病，成为患者和医疗保健系统的巨大负担。目前心力衰竭的治疗重点是通过针对相关的神经体液因素来减缓疾病的进展。虽然成功改善预后，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生和进展有重大影响，因此针对丧失的心肌细胞再生的治疗干预措施保留了巨大的医学前景。为了实现这一目标，近年来，利用各种细胞类型（从骨骼成肌细胞到骨髓干细胞再到内源性心脏干/祖细胞）进行心脏再生的细胞疗法引起了人们的极大兴趣。然而，迄今为止，真正的心脏再生尚未实现，这主要是由于植入时细胞的大量损失以及存活细胞无​​法在敌对和患病的心肌中分化成所需的细胞类型。因此，最大化细胞植入、存活和分化仍然是治疗性心脏再生的最大障碍。有人认为，植入细胞存活率受损可归因于局部微环境或生态位中未能与周围细胞外基质（ECM）网络建立接触。因此，我们假设以 3D 格式在植入的干细胞和 ECM 之间建立接触来模拟培育细胞生态位，不仅会显着改善植入，而且会促进功能分化。在此，我们的目标是采用组合方法开发的系统来系统地操纵封装植入干细胞的局部微环境，目标是优化瞬时细胞生态位以促进分化、保护干细胞并增强植入期间和植入后的植入。 实现真正的心脏再生是一个复杂而艰巨的目标，任何单一实验室都无法单独解决。因此，我们组建了一个研究团队，利用干细胞生物学、心肌生物学和生理学、生物材料科学、生物工程到分子成像等多样化但互补的专业知识，设计了一个综合提案。我们的研究团队拥有长期且富有成效的记录，并将共同努力，通过最大限度地提高干/祖细胞的植入、存活和分化来实现治疗性心脏再生的最终目标。 公共卫生相关性：心血管疾病仍然是发达国家最大的单一死因，在美国夺去的生命比紧随其后的四个主要原因的总和还多。在心血管疾病中，心力衰竭的发病率持续以惊人的速度上升。功能性心肌细胞的丧失对于心力衰竭的发生和进展至关重要。因此，旨在修复和/或再生丢失的心肌细胞的医疗干预措施具有巨大的前景。为了实现这一目标，近年来基于细胞的心脏再生疗法引起了极大的兴趣。然而，迄今为止，真正的心脏再生尚未实现，这主要是由于植入时细胞的大量损失以及存活细胞在不利和患病的微环境中无法分化成所需的细胞类型。我们提案的主要目标是最大限度地提高细胞植入、存活和分化。从我们的提案中获得的数据将为实现治疗性心脏再生的最终目标做出重大贡献。