Creating Super Stem Cells for Cardiac and Wound Repair

创造用于心脏和伤口修复的超级干细胞

• 批准号: 7599501
• 负责人: Pampee P Young
• 金额: $ 34.21万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599501
• 关键词: Address; Biogenesis; Birth; Blood Vessels; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Proliferation; Cell Therapy; Cells; Clinical Trials; Conditioned Culture Media; Data; Deterioration; Development; Down-Regulation; Employee Strikes; Endothelial Cells; Endothelium; Fibroblasts; Functional disorder; Future; Gene Expression; Gene Targeting; Granulation Tissue; Heart; Heart failure; Histologic; Human; Infarction; Injection of therapeutic agent; Intramuscular; Knowledge; Lead; Link; MRL/MpJ Mouse; Mediating; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Muscle; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Pathway interactions; Phenotype; Population; Porifera; Pre-Clinical Model; Reagent; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Stem cells; Therapeutic; Therapeutic Intervention; Tissue Model; Tissues; Transcript; Treatment Efficacy; Wound Healing; Wounds and Injuries; base; diabetic; fetal; human SFRP4 protein; improved; improved functioning; member; migration; novel; older patient; paracrine; preclinical study; reconstitution; regenerative; regenerative therapy; repaired; research study; self-renewal; stem; stem cell population; tool; transdifferentiation; wound

DESCRIPTION (provided by applicant): Until recently, myocardial loss and associated functional deterioration was regarded as irreversible. Yet, accumulating evidence suggests that injected stem cells can improve function of a failing heart, giving birth to a revolutionary concept of regenerative therapy for the heart. Bone marrow (BM)-derived mesenchymal stem cells (MSCs), known to differentiate into a wide variety of tissues, have shown in several preclinical models to result in improved myocardial function leading to a current human clinical trial to provide these dramatic new cell based therapies using human MSCs for myocardial repair. Hence, understanding how to enhance their therapeutic efficacy, e.g. to develop "super" stem cells, would expand their utility, especially in the elderly, patients with cardiac dysfunction, and in the diabetic population in whom stem cell dysfunction has been described. Using a strain that represents the upper end of the regenerative spectrum we isolated MSCs that demonstrate remarkably enhanced regenerative capacity as compared to those from C57Bl/6 (wildtype, WT) mice. The "super" MSCs demonstrated dramatically increased proliferation, vigorous wound tissue reconstitution, and vascular plasticity in a mouse granulation tissue model. Also, soluble factors derived from these cells caused significantly increased proliferation of fetal cardiomyoctyes and migration of endothelial cells over control conditioned media. In a murine myocardial infarct model, intramuscular peri- infarct injection of these cells showed favorable preliminary functional results over WT MSCs and control. We have identified a striking downregulation of the Wnt pathway in the "super" MSCs by differential expression of members of secreted frizzled related proteins and soluble Wnts as compared to WT. We verified both the relative downregulation of Wnt/-catenin signaling in MRLMSCs and that Wnt pathway inhibition enhanced MSC proliferation and granulation tissue formation, implicating this pathway as the molecular basis for the superior regenerative phenotype. We hypothesize that regulation of the Wnt signaling pathway is critical for MSC self-renewal and regenerative capacity. Moreover, we propose that modulating the activity of this pathway will recapitulate the "super stem cell" phenotype and is an excellent future target for cell based therapies for myocardial injuries and wound regeneration.

描述（由申请人提供）：直到最近，心肌损失和相关功能恶化被认为是不可逆转的。然而，越来越多的证据表明，注射干细胞可以改善衰竭心脏的功能，从而产生了心脏再生治疗的革命性概念。骨髓（BM）来源的间充质干细胞（MSCs），已知可以分化成多种组织，在几个临床前模型中显示可以改善心肌功能，导致目前的人类临床试验提供这些戏剧性的新的基于细胞的治疗方法，使用人类MSCs进行心肌修复。因此，了解如何提高它们的治疗效果，例如开发“超级”干细胞，将扩大它们的用途，特别是在老年人、心功能障碍患者和已经描述了干细胞功能障碍的糖尿病人群中。使用代表再生谱上端的菌株，我们分离的MSCs与C57Bl/6（野生型，WT）小鼠相比，表现出显著增强的再生能力。在小鼠肉芽组织模型中，“超级”MSCs表现出显著的增殖、强劲的伤口组织重建和血管可塑性。此外，来源于这些细胞的可溶性因子显著增加了胎儿心肌细胞的增殖和内皮细胞在对照条件培养基上的迁移。在小鼠心肌梗死模型中，肌内注射这些细胞比WT间充质干细胞和对照组显示出良好的初步功能结果。与WT相比，我们通过分泌卷曲相关蛋白和可溶性Wnt成员的差异表达，发现了“超级”MSCs中Wnt通路的显著下调。我们验证了MRLMSCs中Wnt/-catenin信号的相对下调，以及Wnt通路抑制增强了MSC增殖和肉芽组织形成，暗示该通路是优越再生表型的分子基础。我们假设Wnt信号通路的调节对MSC自我更新和再生能力至关重要。此外，我们提出，调节这一途径的活性将概括“超级干细胞”表型，是未来基于细胞治疗心肌损伤和伤口再生的一个很好的目标。