iPSC-Derived Endothelial Progenitor Cell Treatment of Lung Vascular Injury

iPSC 衍生的内皮祖细胞治疗肺血管损伤

• 批准号: 8680314
• 负责人: Asrar B. Malik
• 金额: $ 38.47万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680314
• 关键词: Acute; Acute Lung Injury; Address; Blood Vessels; Cell Surface Proteins; Cell Therapy; Cell physiology; Cell surface; Cells; Cessation of life; Databases; Disease; Edema; Effectiveness; Embryo; Engraftment; Fibroblasts; Fluid Balance; Hematopoietic stem cells; Human; In Situ; Infiltration; Inflammation; Inflammatory; Injury; Integrins; Intervention; Lead; Life; Ligation; Liquid substance; Lung; Lung Inflammation; Mediating; Memory; Mesenchymal; Mesoderm; Modeling; Molecular; Molecular Profiling; Mus; Natural regeneration; Population; Program Development; Proteins; Pseudomonas; Puncture procedure; Recovery; Relative (related person); Research Personnel; Role; Safety; Secondary to; Sepsis; Skin; Stem cells; Testing; Therapeutic; Time; Transplantation; Ursidae Family; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; base; cadherin 5; induced pluripotent stem cell; injured; innovation; lung injury; lung vascular injury; mortality; mouse model; precursor cell; prevent; progenitor; protective effect; regenerative; repaired; research study; response; restoration

DESCRIPTION (provided by applicant): The ability to generate induced pluripotent stem cells (iPSCs) from skin fibroblasts and other mature cells and then to drive them to distinct lineages brings closer the promise of cell based therapies. Here we propose to test the feasibility of using iPSC-derived endothelial progenitor cells (EPCs) alone or in conjunction with hematopoietic stem cells (HSCs) to induce restoration of lung endothelial barrier function and regeneration of lung vessels after lung injury induced by sepsis. We will also define the molecular and cellular mechanisms mediating endothelial barrier and vascular repair induced by the iPSC-derived progenitors. The possibility of using iPSC-derived progenitor cells represents a quantal advancement over current approaches employing the difficult to obtain and controversial ESC-derived cells or mesenchymal cells with consequences and short-lived humorally-mediated actions. However, there are fundamental questions concerning the use, safety, and mechanism of action of iPSC- derived cells, which this proposal hopes to address. These questions include do these progenitors cells have a "memory" of their origin, do they function as effectively as ESC-derived progenitor cells when differentiated into EPCs, are their effects secondary to engraftment in the injured lung niche and/or humoral mechanisms, do they repair the injured endothelial barrier and lung vessels and if so how. The studies are based on our ability to differentiate iPSCs to a relatively pure population of EPCs (which are positive for both Flk1 and VE-cadherin markers) and are characterized by their ability to form an endothelial barrier and produce blood vessels. We propose the following aims: Aim 1, To address the endothelial barrier protective and vascular regenerative potential of mouse iPSCs differentiated into EPCs and HSCs; Aim 2, To determine the role of iPSC-derived EPCs in restoring lung microvascular barrier function and fluid balance in sepsis; and Aim 3, To determine the role of iPSC-derived progenitor cells in mediating microvascular regeneration after lung vascular injury. These studies will be made using diverse approaches requiring the efforts and expertise of a team of outstanding multi-disciplinary investigators and consultants, with the hope of providing the scientific rationale for iPSC-based therapy targeted against acute inflammatory injury.

描述（由申请人提供）：从皮肤成纤维细胞和其他成熟细胞中产生诱导多能干细胞（IPSC）的能力，然后将它们驱动到独特的谱系使基于细胞的疗法的承诺更加接近。在这里，我们建议单独使用IPSC来源的内皮祖细胞（EPC）或与造血干细胞（HSC）一起诱导肺部内皮屏障功能和肺部受伤后的肺部血管的再生。我们还将定义介导由IPSC衍生的祖细胞引起的内皮屏障和血管修复的分子和细胞机制。使用IPSC衍生的祖细胞的可能性代表了使用难以获得和有争议的ESC衍生细胞或间充质细胞的当前方法的量化进步，并具有后果和短暂的幽默介导的作用。但是，有关IPSC衍生细胞的使用，安全性和作用机理的基本问题，该提案希望解决。这些问题包括这些祖细胞对其起源的“记忆”，当分化为EPC时，它们是否像ESC衍生的祖细胞一样有效地起作用，是其继发于受伤的肺壁细菌和/或体液机制的效果，它们是否修复受伤的内皮障碍和肺部和肺部和肺部和肺部以及如何修复。这些研究基于我们将IPSC与相对纯净的EPC种群区分开的能力（对于FLK1和VE-Cadherin标记均为阳性），其特征是它们形成内皮屏障并产生血管的能力。我们提出以下目的：目标1，以解决小鼠IPSC的内皮屏障保护和血管再生潜力，分为EPC和HSC； AIM 2，确定IPSC衍生的EPC在恢复败血症中肺微血管屏障功能和流体平衡中的作用；和AIM 3，以确定IPSC衍生的祖细胞在肺血管损伤后介导微血管再生中的作用。这些研究将采用多种方法进行，需要一组杰出的多学科研究人员和顾问团队的努力和专业知识，以期为针对抗急性炎症性损伤的基于IPSC的治疗提供科学原理。