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: 8242088
• 负责人: Pampee P Young
• 金额: $ 33.83万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242088
• 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; cardiac repair; 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的。然而，积累的证据表明，注射干细胞可以改善心脏失败的功能，从而孕育着对心脏再生治疗的革命性概念。骨髓（BM）衍生的间充质干细胞（MSC）（已知分化为多种组织）在几种临床前模型中显示，以改善心肌功能，从而改善了人类临床试验，从而提供了这些戏剧性的基于细胞的新细胞疗法，该疗法使用人类MSC进行心肌修复。因此，了解如何增强其治疗功效，例如为了开发“超级”干细胞，将扩大其效用，尤其是在老年人，心脏功能障碍的患者以及已描述了干细胞功能障碍的糖尿病患者中。与C57BL/6（Wildtype，wt）小鼠相比，使用代表再生光谱上端的菌株，我们分离了MSC。 “超级” MSC在小鼠颗粒组织模型中显示出大量增加的增殖，剧烈的伤口组织重建和血管可塑性。同样，从这些细胞中得出的可溶性因子导致胎儿心肌的增殖显着增加，而内皮细胞在对照培养基上的迁移。在鼠心肌梗塞模型中，这些细胞的肌肉内梗塞注射显示出比WT MSC和对照的有利的初步功能结果。与WT相比，我们已经确定了“超级” MSC中WNT途径的引人注目的下调。我们验证了MRLMSC中Wnt/ - 蛋白质信号传导的相对下调，Wnt途径抑制增强了MSC增殖和颗粒组织的形成，这意味着该途径是上等再生表型的分子基础。我们假设Wnt信号通路的调节对于MSC自我更新和再生能力至关重要。此外，我们提出调节该途径的活性将概括“超级干细胞”表型，并且是基于细胞的心肌损伤和伤口再生的极好的未来靶标。

项目成果

Increased oxygen consumption and OXPHOS potential in superhealer mesenchymal stem cells.

超级治疗间充质干细胞的耗氧量和 OXPHOS 潜力增加。

• DOI: 10.1186/2045-9769-1-3
• 发表时间: 2012
• 期刊: Cell regeneration (London, England)
• 作者: Hughey,CurtisC;Alfaro,MariaP;Belke,DarrellD;Rottman,JefferyN;Young,PampeeP;Wasserman,DavidH;Shearer,Jane
• 通讯作者: Shearer,Jane

TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin.

• DOI: 10.1158/1541-7786.mcr-10-0484
• 发表时间: 2011-06
• 期刊: Molecular cancer research : MCR
• 作者: Li B;Pozzi A;Young PP
• 通讯作者: Young PP