3D combinatorial microenvironments for effective cell based therapy

描述（由申请人提供）：心力衰竭是患病率和发病率持续上升的唯一心血管疾病，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主要集中在通过靶向神经体液因素来减缓疾病的进展。在成功改善预后的同时，发病率和死亡率仍然很高。由于功能性心肌细胞的丧失显著促进心力衰竭的发展和进展，因此针对丧失的心肌细胞再生的治疗干预保留了巨大的医学前景。为了实现这一目标，近年来，采用各种细胞类型（从骨骼肌成肌细胞到骨髓源性干细胞到内源性心脏干/祖细胞）的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，这主要是由于在植入时细胞的显著损失以及存活细胞不能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。这表明，植入细胞的存活受损可归因于在局部微环境或生态位中与周围细胞外基质（ECM）网络建立接触的失败。因此，我们假设在植入的干细胞和ECM之间以3D形式建立接触以模拟培育细胞小生境不仅会显着改善植入，而且会促进功能分化。在此，我们的目标是采用使用组合方法开发的系统来系统地操纵封装植入的干细胞的局部微环境，目标是优化瞬时细胞小生境以促进分化，保护干细胞并在植入期间和之后增加植入。 实现真正的心脏再生是一个复杂和过度的目标，任何单一的实验室都无法单独解决。因此，我们组建了一个研究团队，并设计了一个综合方案，利用干细胞生物学、心肌生物学和生理学、生物材料科学、生物工程和分子成像等多种但互补的专业知识。我们的研究团队拥有长期和富有成效的跟踪记录，并将共同努力，通过最大限度地提高干/祖细胞植入，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死亡原因，在美国，死亡人数超过了四个主要原因的总和。在心血管疾病中，心力衰竭的发病率继续以惊人的速度上升。功能性心肌细胞的丧失对心力衰竭的发展和进展至关重要。因此，以修复和/或再生丢失的心脏细胞为目标的医疗干预具有巨大的前景。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，这主要是由于在植入时细胞的显著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。我们建议的主要目标是最大限度地提高细胞移植，存活和分化。从我们的提案中获得的数据将大大有助于实现治疗性心脏再生的最终目标。

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.