Monitoring of Stem Cell Engraftment in Arthritic Joints with MR Imaging

描述（由申请人提供）：美国目前约有4300万人因关节炎而残疾。软骨缺损是受影响关节疼痛的主要来源。目前的治疗，虽然减轻了一些临床症状，证明不足以 治愈潜在的不可逆的软骨损失。干细胞是修复软骨缺损的独特来源。然而，干细胞和软骨细胞移植的各种方法的主要挑战是移植细胞的死亡与免疫系统的清除。本项目的总体目标是开发一种非侵入性和临床适用的MR成像技术，该技术可提供基质相关干细胞植入物（马西）植入过程并发症的早期诊断。假设关节炎关节中的存活和凋亡马西在MR图像上表现出不同的信号特征，当与细胞特异性MR造影剂结合时。在我们目前的资助期内，我们已经建立了氧化铁纳米颗粒和钆螯合物干细胞移植的标记技术，我们已经定义了标记的活性和凋亡马西的不同信号特征。在新的资助期间，我们将继续使用这种方法来识别和开发用于临床转化的强候选造影剂。我们计划在新的资助期结束前申请IND，用于最有前途的方法的临床转化。在我们追求临床适用的成像方法中，我们将首先通过用FDA批准的氧化铁纳米颗粒ferumoxytol（Feraheme）直接标记移植的干细胞来评估马西后早期的干细胞损失和/或凋亡。在第二步中，我们将评估一种新型半胱天冬酶敏感的MR造影剂在关节造影成像方法中检测马西中干细胞凋亡的敏感性。在第三步中，我们将通过MR检测氧化铁标记的骨髓巨噬细胞迁移到马西中来间接识别失败的马西。将进行补充光学成像研究以及共聚焦显微镜、免疫组织化学和光谱学研究，以阐明导致观察到的MR信号特征的所研究细胞移植物的生物学和理化变化。这些结果将有助于临床前评估新的基于干细胞的关节炎治疗方法，设计相关的临床试验， hMSC治疗关节炎，并最终在临床实践中评估那些hMSC治疗方案。通过开发新的，临床上适用的细胞跟踪技术作为一种新的非侵入性体内监测干细胞植入结果的方法，我们预计将显著改善和加速患者软骨再生成功疗法的发展，并最终减轻长期残疾和我们社会的相关成本。由于我们提出了一个广义的干细胞植入成像的新概念，结果可能不仅影响马西患者，而且影响各种其他（干）细胞移植的患者。

DESCRIPTION (provided by applicant): About 43 million individuals in the US currently suffer from disabilities due to arthritis. Cartilage defects are the major source of pain in the affected joints. Current treatments, whilst alleviating some of the clinical symptoms, prove insufficient to cure the underlying irreversible cartilage loss. Stem cells represent a unique source for restoration of cartilage defects. However, a major challenge with various approaches of stem cell and chondrocyte transplants is death of the transplanted cells with clearance by the immune system. The overall goal of this project is to develop a non-invasive and clinically applicable MR imaging technique, which provides an early diagnosis of complications of the engraftment process of matrix associated stem cell implants (MASI). The hypothesis is that viable and apoptotic MASI in arthritic joints demonstrate distinct signal characteristics on MR images, when combined with cell-specific MR contrast agents. In our current funding period, we have established labeling techniques for stem cell transplants with iron oxide nanoparticles and gadolinium chelates, and we have defined distinct signal characteristics of labeled viable and apoptotic MASI. During the new funding period, we will continue to use this approach to identify and develop strong candidate contrast agents for clinical translation. We plan to apply for an IND for clinical translation of the most promising approach by the end of this new funding period. In our pursuit of clinically applicable imaging approaches, we will first evaluate stem cell loss and/or apoptosis early after MASI via direct labeling of transplanted stem cells with the FDA-approved iron oxide nanoparticle ferumoxytol (Feraheme). In a second step, we will evaluate a novel caspase-sensitive MR contrast agent regarding its sensitivity to detect stem cell apoptosis in MASI with an arthrographic imaging approach. In a third step, we will identify failed MASI indirectly, via MR detection of the migration of iron oxide labeled bone marrow macrophages into MASI. Complementary optical imaging studies as well as confocal microscopy, immunohistochemistry and spectrometry studies will be performed to elucidate biological and physicochemical changes of the investigated cell transplants that lead to the observed MR signal characteristics. Results should be immediately helpful in the preclinical assessment of new stem cell based therapies for arthritis treatment, in the design of related clinical trials for hMSC therapy of arthritis, and ultimately, in the assessment of those hMSC therapy regimens in clinical practice. By exploiting novel, clinically applicable cell tracking techniques as a new too to monitor stem cell engraftment outcomes non-invasively in vivo, we anticipate significantly improving and accelerating the development of successful therapies for cartilage regeneration in patients, and ultimately, alleviating long term disabilities and related costs to our society. Sinc we address a generalized novel concept for imaging stem cell engraftment, results might not only impact patients with MASI but also patients with a variety of other (stem) cell transplants.