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（由申请人提供）：每年，关节炎导致 4400 万人次门诊就诊和 700,000 例膝关节置换手术。软骨缺损的早期修复可以防止关节进一步恶化，并避免日后进行膝关节置换手术。间充质干细胞（MSC）已在软骨修复手术中取得了一些成功，间充质干细胞可以很容易地从接受软骨修复手术的患者的骨髓中获得。并已被证明可以直接或间接介导软骨修复，但是，软骨缺损中很大一部分 MSC 植入物无法植入，目前尚无可用的诊断测试可以监测细胞植入患者膝盖后的植入情况。目前，干细胞移植的成功是在移植后几个月通过评估软骨修复和功能重建的程度来诊断的，这是一种可以可视化和监测移植的 MSC 存在的成像方法。直接、非侵入性、纵向地体内靶位点 将极大地增强我们了解 MSC 介导的组织再生过程的能力，并使我们能够在疤痕组织尚未形成并且可以进行重复干预的早期时间点检测失败的移植。因此，该项目的主要目标是。开发一种新的、可立即临床转化的 MR 成像生物标志物，用于早期检测 MASI 失败，迄今为止，用于非侵入性成像的标记 MSC 的唯一方法需要在实验室中进行操作。造影剂，水洗，这些操作对于临床转化来说是有问题的，因为它可能导致细胞的生物学改变或污染，该技术涉及在提取细胞驻留在供体骨髓中时对其进行标记。这种新的体内标记方法基于在干细胞收获之前简单静脉注射铁补充剂（ferumoxytol，Feraheme），并且不需要在骨髓收获和移植之间对 MSC 进行任何操作在分两步的方法中，我们将首先在猪模型中评估体内标记的自体 MSC 的软骨修复结果，接下来，我们将评估干细胞介导的 MR 信号的早期消失是否相关。如果成功，这些研究将直接导致临床转化，加速对软骨修复不成功风险的 MASI 的检测，帮助识别改善软骨再生结果的干预措施，以及最终，改善关节炎关节的形态和功能重建。