Tracking Mesenchymal Stem Cells with MR Imaging: Clinical Translation

 描述(申请人提供)：每年，关节炎患者的门诊就诊次数达到4400万人次，膝关节置换手术达到70万例。早期修复软骨缺陷可能会防止关节进一步恶化，并在以后的生活中防止膝关节置换手术的需要。间充质干细胞(MSC)已成功应用于软骨修复过程中。骨髓间充质干细胞可以很容易地从正在接受软骨修复程序的患者的骨髓中获得，并已被证明直接或间接地介导软骨修复。然而，相当大比例的MSC植入物在软骨缺损中无法植入。目前还没有可用的诊断测试来监测细胞在患者膝关节损伤部位沉积后的植入情况。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判断的。一种可直接、非侵入性、纵向监测体内移植MSC存在的成像方法 这将极大地提高我们了解MSC介导的组织再生过程的能力，并使我们能够在瘢痕组织尚未形成且可能进行反复干预的早期时间点检测到失败的移植。因此，该项目的主要目标是开发一种新的、可立即在临床上翻译的磁共振成像生物标记物，用于早期发现MASI衰竭。到目前为止，标记MSCs进行非侵入性成像的唯一方法需要在实验室进行操作。在提取时，细胞必须与造影剂孵育，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变化或污染。我们最近开发了一种新技术，包括在提取细胞之前对它们进行标记，而这些细胞驻留在捐赠者的骨髓中。这种新的体内标记方法基于干细胞采集前简单的静脉注射铁补充剂(阿魏酸甘油酯、亚铁血红素)，在从采集骨髓到移植到关节炎关节之间不需要对MSC进行任何操作。在两个步骤的方法中，我们将首先评估体内标记的自体MSC在猪模型中的MR信号特征和软骨修复结果。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丢失和软骨修复不完全的结果相关。如果成功，这些研究将直接导致临床翻译，将加速检测MASI存在不成功软骨修复的风险，有助于识别改善软骨再生结果的干预措施，并最终改善关节炎关节的形态和功能重建。

 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.