Tracking Mesenchymal Stem Cells with MR Imaging: Clinical Translation

利用 MR 成像追踪间充质干细胞：临床转化

• 批准号: 8845999
• 负责人: Heike Elizabeth Daldrup-Link
• 金额: $ 21.96万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-11 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845999
• 关键词: Accounting; Affect; Animal Model; Animals; Apoptosis; Apoptosis Promoter; Apoptotic; Arthritis; Aspirate substance; Autologous; Biological; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cartilage; Cell Death; Cells; Cellular biology; Characteristics; Cicatrix; Clinical; Contrast Media; Data; Defect; Deposition; Detection; Deterioration; Development; Diagnosis; Diagnostic tests; Direct Costs; Early Diagnosis; Endothelium; Engraftment; Evaluation; FDA approved; Facilities and Administrative Costs; Failure; Family suidae; Fibrocartilages; Goals; Harvest; Hematopoietic; Histologic; Hospitalization; Hour; Hyaline Cartilage; Image; Imaging technology; Implant; Implantation procedure; In Vitro; Incubated; Individual; Injection of therapeutic agent; Intervention; Intravenous; Investigation; Iron; Joint repair; Joints; Kinetics; Knee Injuries; Knee joint; Label; Laboratories; Lead; Life; Magnetic Resonance Imaging; Mechanics; Mediating; Medical; Mesenchymal Stem Cells; Mitomycins; Modeling; Monitor; Natural regeneration; Non-Invasive Cancer Detection; Orthopedics; Outcome; Outpatients; Pain; Patients; Procedures; Process; Regression Analysis; Risk; Rodent; Sampling; Signal Transduction; Site; Source; Stem cell transplant; Stem cells; Surgeon; Techniques; Time; Tissues; Toxic effect; Transfection; Translations; Transplantation; United States; Visit; base; cartilage regeneration; cartilage repair; disability; ferumoxytol; imaging biomarker; imaging modality; improved; in vivo; intravenous administration; intravenous injection; iron supplement; knee replacement arthroplasty; non-invasive imaging; prevent; public health relevance; reconstitution; repaired; stem cell biology; success; tissue regeneration; uptake

 DESCRIPTION (provided by applicant): Every year, arthritis accounts for 44 million outpatient visits and 700,000 knee-replacement procedures. Early repair of cartilage defects may prevent further deterioration of the joint and the need for knee replacement procedures later in life. Mesenchymal stem cells (MSC) have been used with some success in cartilage-repair procedures. MSC can be easily derived from bone marrow of patients who are undergoing a cartilage-repair procedure and have been shown to directly or indirectly mediate cartilage repair. However, a significant proportion of MSC implants in cartilage defects fail to engraft. There is currently no diagnostic test available that could monitor the cells' engraftment after they are deposited at a patient's knee-injury site. Currently, the success of stem cell transplants is diagnosed several months after their transplantation by evaluation of the degree of cartilage repair and functional reconstitution. An imaging method that could visualize and monitor the presence of transplanted MSC at the target site directly, non-invasively and longitudinally in vivo would greatly enhance our ability to understand MSC-mediated tissue regeneration processes and enable us to detect failed transplants at an early time point, when scar tissue has not formed yet and a repeated intervention would be possible. Thus, the major goal of this project is to develop a new and immediately clinically translatable MR imaging biomarker for early detection of MASI failure. Until now, the only ways of labeling MSCs for non-invasive imaging have required their manipulation in the laboratory. Upon extraction, the cells had to be incubated with contrast agents, washed, centrifuged and then transplanted. These manipulations are problematic for clinical translation because it could lead to biological alterations or contaminations of the cells. We have recently developed a new technique, which involves labeling the cells before extraction, while they reside in the donor's bone marrow. This new in vivo labeling approach is based on simple intravenous administration of an iron supplement (ferumoxytol, Feraheme) prior to stem cell harvest and does not require any manipulations of MSC between harvest from bone marrow and transplantation into arthritic joints. In a two- step approach, we will first evaluate MR signal characteristics and cartilage repair outcomes of in vivo labeled autologous MSC in a porcine model. Next, we will evaluate if early disappearance of the stem cell-mediated MR signal correlates with stem cell loss and incomplete cartilage repair outcomes. If successful, these studies will directly lead to clinical translation, will accelerate detection of MASI at risk for unsuccessful cartilage repair, help to recognize interventions that improve cartilage regeneration outcomes, and ultimately, improve morphological and functional reconstitution of arthritic joints.

 描述（由适用提供）：每年，关节炎占4400万个门诊就诊和70万膝盖替代程序。软骨缺陷的早期修复可能会阻止关节进一步恶化，并且需要在以后的生活中进行膝盖置换程序。间充质干细胞（MSC）已在软骨修复程序中成功使用。 MSC可以很容易地从正在接受软骨修复程序的患者的骨髓中得出，并已直接或间接显示了培养基软骨修复。但是，软骨缺陷中的MSC牙齿中很大一部分未能植入。目前尚无可用的诊断测试，可以在病人的膝盖伤害部位沉积后可以监测细胞的植入。目前，通过评估软骨修复程度和功能重构程度，干细胞移植后几个月诊断出了干细胞移植的成功。一种成像方法，可以直接，非侵入性和纵向在体内可视化和监视目标位点上移植的MSC的存在 将大大增强我们了解MSC介导的组织再生过程的能力，并使我们能够在尚未形成疤痕组织的早期时间内检测到失败的移植物，并且可以重复干预。这是该项目的主要目标是开发一种新的临床翻译成MR成像生物标志物以早期检测MASI衰竭的方法。到目前为止，为非侵入成像标记MSC的唯一方法需要在实验室中操纵。提取后，必须将细胞与对比剂孵育，洗涤，离心然后移植。这些操作对于临床翻译是有问题的，因为它可能导致细胞的生物学改变或污染。我们最近开发了一种新技术，该技术涉及在提取前将细胞标记，而它们居住在供体的骨髓中。这种新的体内标记方法基于干细胞收获之前的简单静脉内给药（Ferumoxytol，feraheme），并且不需要从骨髓和移植到关节炎关节中收获的MSC进行任何操作。在两步方法中，我们将首先评估猪模型中体内标记自体MSC的MR信号特性和软骨修复结果。接下来，我们将评估干细胞介导的MR信号的早期消失是否与干细胞损失和不完全的软骨修复结果相关。如果成功的话，这些研究将直接导致临床翻译，将加速对软骨修复的风险的MASI检测，有助于识别改善软骨再生结果的干预措施，并最终改善Artritic关节的形态和功能重新建立。