Engineered Induction of a Stem Cell Homing Response

干细胞归巢反应的工程诱导

• 批准号: 7886427
• 负责人: Jeffrey Michael Karp
• 金额: $ 45.39万
• 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: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886427
• 关键词: Adhesions; Adhesives; Affect; Antibodies; Biotin; Blood Circulation; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiovascular Diseases; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Survival; Cell Therapy; Cell surface; Cells; Cessation of life; Characteristics; Chemicals; Clinical; Congestive Heart Failure; Connective Tissue; Data; Defect; Deterioration; Development; Disease; Endothelial Cells; Endothelium; Engineering; Engraftment; Ethics; Extravasation; Glycoproteins; Goals; Heart; Home environment; Homing; Human; In Vitro; Infarction; Inflammation; Injection of therapeutic agent; Integrins; Intercellular adhesion molecule 1; Lead; Leukocytes; Ligands; Literature; Mediating; Mesenchymal Stem Cells; Methods; Modeling; Modification; Molecular; Mus; Myocardial Infarction; Myocardium; Natural regeneration; P-Selectin; P-selectin ligand protein; Play; Property; Quality of life; Role; Selectins; Simulate; Site; Source; Stem cells; Streptavidin; Surface; Tail; Therapeutic; Tissues; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; Veins; Work; Wound Healing; cell type; design; improved; improved functioning; in vivo; interest; migration; mouse model; novel strategies; paracrine; public health relevance; receptor; repaired; research study; response; shear stress; sialyl Lewis a; stem cell therapy; surface coating; trafficking

DESCRIPTION (provided by applicant): There is a great need for therapeutic strategies that aid in the repair or regeneration of ischemic tissue following myocardial infarction, especially therapies that can improve the engraftment of therapeutic cells (i.e. stem cells). Myocardial infarction typically leads to death of cardiomyocytes in the infarct zone that culminates in pathological remodeling of the heart. This can cause severe consequences such as cardiac dilation, wall thinning and deterioration of contractile function leading to congestive heart failure. Therapeutic strategies that aim to harness or enhance (with an exogenous cell source) natural stem cell homing mechanisms show promise to preserve and restore cardiac output following myocardial infarction. Although results in human trials are mixed, certain negative results may be explained by inefficient homing mechanisms. We have recently developed a simple platform strategy that can be used to effectively incorporate potentially any homing receptor onto a cell surface for systemic cell targeting. We have shown that incorporation of homing receptors onto the surface of mesenchymal stem cells (MSCs) can lead to a robust homing response which we have characterized via in vitro cell rolling experiments under physiologically simulated conditions. We have also shown that our approach can be used to significantly enhance the homing of systemically infused MSCs within a murine model of inflammation. Importantly, we have determined modification conditions that maintain MSC viability, cell adhesion, proliferation, and multi-differentiation capacities. The goal of this work is to engineer the surface of MSCs to enhance their trafficking efficiency to site of cardiovascular disease, and improve the homogeneity of the homing response without affecting their native properties, including their ability to transmigrate through vascular endothelium. Our initial efforts will focus on attaching biotinylated ligands to induce a robust cell rolling response. To emigrate to extravascular spaces, circulating cells must rapidly develop strong adhesion to, and arrest on specific sites of vascular endothelium while resisting continuous shear forces at the vessel walls. Since selecting-dependent adhesion of leukocytes does not lead to firm adhesion and transmigration unless another set of adhesion molecules, the integrins, are engaged, we plan to co-immobilize rolling ligands with antibodies that target integrins that are expressed on endothelium at sites of inflammation or within ischemic tissue. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to engineer the surface of mesenchymal stem cells to enhance their trafficking efficiency to sites of cardiovascular disease, and improve the homogeneity of the homing response without affecting their native properties, including their ability to transmigrate through vascular endothelium and capacity for multi-lineage differentiation. The development of this novel approach will have broad implications for wound repair and treatment of many tissues where cell based therapies is appropriate. Potential benefits for treatment of ischemic tissue following myocardial infarction include increased cardiac output leading to increased survival and improved quality of life.

描述（由申请人提供）：非常需要有助于心肌梗死后缺血组织修复或再生的治疗策略，特别是可以改善治疗性细胞（即干细胞）植入的疗法。心肌梗死通常导致梗死区心肌细胞死亡，最终导致心脏的病理性重塑。这可能导致严重的后果，如心脏扩张，壁变薄和收缩功能恶化，导致充血性心力衰竭。旨在利用或增强（外源性细胞来源）天然干细胞归巢机制的治疗策略有望在心肌梗死后保持和恢复心输出量。虽然人体试验的结果好坏参半，但某些负面结果可能是由无效的归巢机制解释的。我们最近开发了一种简单的平台策略，可用于有效地将任何归巢受体潜在地整合到细胞表面上，用于系统性细胞靶向。我们已经表明，归巢受体到间充质干细胞（MSC）的表面上的掺入可以导致一个强大的归巢反应，我们已经通过在体外细胞滚动实验在生理模拟条件下的特点。我们还表明，我们的方法可用于显著增强全身输注的MSC在小鼠炎症模型中的归巢。重要的是，我们已经确定了维持MSC活力、细胞粘附、增殖和多分化能力的修饰条件。 这项工作的目标是设计MSC的表面，以提高其运输效率到心血管疾病部位，并提高归巢反应的均匀性，而不影响其天然特性，包括其通过血管内皮的能力。我们最初的努力将集中在连接生物素化配体，以诱导一个强大的细胞滚动反应。为了迁移到血管外空间，循环细胞必须迅速形成与血管内皮的特定位点的强粘附，并在血管内皮的特定位点上停滞，同时抵抗血管壁处的连续剪切力。由于白细胞的选择依赖性粘附不会导致牢固的粘附和迁移，除非另一组粘附分子，整合素，参与，我们计划共同识别配体与抗体的目标整合素，表达在内皮上的炎症部位或缺血组织内。 公共卫生关系：该提案的目的是设计间充质干细胞的表面，以提高其向心血管疾病部位的运输效率，并提高归巢反应的均一性，而不影响其天然特性，包括其通过血管内皮的迁移能力和多谱系分化的能力。这种新方法的发展将对伤口修复和许多组织的治疗产生广泛的影响，其中基于细胞的治疗是合适的。治疗心肌梗死后缺血组织的潜在获益包括增加心输出量，从而提高生存率和改善生活质量。