Musculoskeletal Applications of Iron Loading for Stem Cell Tracking with Magnetic Resonance Imaging

Stem cells have shown promise for tissue regeneration in a variety of pathological conditions. Specifically, mesenchymal stem cells have demonstrated the ability to promote tissue repair of the musculoskeletal system through differentiation along specific lineages including bone, cartilage, muscle, and fat. As part of the ongoing development of stem cell therapies and the gradual transition of these techniques into the clinic, it is crucial to be able to monitor these cells following implantation into the body. Magnetic resonance imaging (MRI) has the capability to provide in vivo non-invasive imaging of cells at multiple time points following implantation. As such, these research studies focus on the development of techniques to generate contrast between cells and the surrounding environment on MR images using iron-based methods. In particular, these studies focus on the application of such techniques to stem cell tracking for tissue engineering of the musculoskeletal system. The techniques investigated include cell loading with iron oxide-based contrast agents of various sizes as well as genetic engineering strategies to increase iron uptake through modified protein expression. Studies using iron oxides demonstrate the ability to non-toxically label cells, detect them via MRI, and quantitatively characterize signal loss associated with labeling. However, issues with excess particles following labeling could potentially hinder the accuracy of this approach. Furthermore, aggregation of excess particles during in vitro stem cell differentiation precludes the ability to utilize conventional staining techniques to assess the effect of labeling on differentiation capacity. Genetic engineering studies on (non-stem cell) mammalian cells suggest no effect on iron uptake resulting from expression of the bacterial gene magA. However, ferritin up-regulation results in increased iron uptake in transiently transfected cells, but not enough to enable MRI detection. Further studies focused on generation of ferritin expressing stable cell lines as well as cells expressing gene combinations known to play a role in iron uptake are warranted. While significant research is still necessary before iron loading techniques can be transitioned into a clinical setting, the promising results of these studies and the clear potential benefits of its successful development are a strong motivation for continued investigation