Tracking Mesenchymal Stem Cells with MR Imaging: Clinical Translation

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 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.