Tracking Mesenchymal Stem Cells with MR Imaging: Clinical Translation

 描述（由申请人提供）：每年，关节炎占4400万门诊和70万膝关节置换手术。软骨缺损的早期修复可以防止关节的进一步恶化和以后生活中对膝关节置换手术的需要。间充质干细胞（MSC）已在软骨修复程序中取得了一些成功。MSC可以很容易地从正在接受软骨修复手术的患者的骨髓中获得，并且已经显示出直接或间接介导软骨修复。然而，在软骨缺损中的MSC植入物的显著比例未能植入。目前还没有诊断测试可以监测细胞在患者膝盖受伤部位沉积后的植入情况。目前，通过评估软骨修复和功能重建的程度，在移植后几个月诊断干细胞移植的成功。一种成像方法，可以直接，非侵入性和纵向体内观察和监测移植MSC在靶部位的存在 将大大提高我们理解MSC介导的组织再生过程的能力，并使我们能够在早期时间点检测失败的移植，此时瘢痕组织尚未形成，并且可以重复干预。因此，本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，用于早期检测马西失败。到目前为止，标记MSC用于非侵入性成像的唯一方法需要在实验室中对其进行操作。提取后，细胞必须与造影剂一起孵育，洗涤，离心，然后移植。这些操作对于临床转化是有问题的，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，包括在提取前标记细胞，而它们驻留在捐赠者的骨髓中。这种新的体内标记方法基于在干细胞收获之前简单静脉内施用铁补充剂（ferumoxytol，Feraheme），并且在从骨髓收获和移植到关节炎关节中之间不需要MSC的任何操作。在一个两步的方法中，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不完全软骨修复结果相关。如果成功，这些研究将直接导致临床转化，将加速检测有软骨修复失败风险的马西，帮助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.