In vivo cell tracking by MRI can provide means to observe biological processes and monitor cell therapy directly. Immune cells, e.g., macrophages, play crucial roles in many pathophysiological processes, including organ rejection, inflammation, autoimmune diseases, cancer, atherosclerotic plaque formation, numerous neurological disorders, etc. The current gold standard for diagnosing and staging rejection after organ transplantation is biopsy, which is not only invasive, but also prone to sampling errors. Here, we report a noninvasive approach using MRI to detect graft rejection after solid organ transplantation. In addition, we present the feasibility of imaging individual macrophages in vivo by MRI in a rodent heterotopic working-heart transplantation model using a more sensitive contrast agent, the micrometer-sized paramagnetic iron oxide particle, as a methodology to detect acute cardiac rejection.cardiac rejection ͉ detection of single macrophage ͉ micrometer-sized iron oxide particle ͉ nanometer-sized iron oxide particle
The 18kDa Translocator Protein (TSPO) is the most commonly used tissue-specific marker of inflammation in positron emission tomography (PET) studies. It is expressed in myeloid cells such as microglia and macrophages, and in rodent myeloid cells expression increases with cellular activation. We assessed the effect of myeloid cell activation on TSPO gene expression in both primary human and rodent microglia and macrophages in vitro, and also measured TSPO radioligand binding with 3H-PBR28 in primary human macrophages. As observed previously, we found that TSPO expression increases (∼9-fold) in rodent-derived macrophages and microglia upon pro-inflammatory stimulation. However, TSPO expression does not increase with classical pro-inflammatory activation in primary human microglia (fold change 0.85 [95% CI 0.58–1.12], p = 0.47). In contrast, pro-inflammatory activation of human monocyte-derived macrophages is associated with a reduction of both TSPO gene expression (fold change 0.60 [95% CI 0.45–0.74], p = 0.02) and TSPO binding site abundance (fold change 0.61 [95% CI 0.49–0.73], p < 0.0001). These findings have important implications for understanding the biology of TSPO in activated macrophages and microglia in humans. They are also clinically relevant for the interpretation of PET studies using TSPO targeting radioligands, as they suggest changes in TSPO expression may reflect microglial and macrophage density rather than activation phenotype.
Purpose: To evaluate cellular labeling of immune cells using micron-sized iron oxide particles (MPIOs) and evaluate the MR relaxivity and MRI detection of the labeled cells.
Materials and Methods:Immune cells isolated from mice and rats were labeled with three different sizes of MPIO particles (0.35, 0.90, or 1.63 m). These labeled cells were characterized using transmission electron microscopy (TEM), fluorescence microscopy, flow cytometry, MR relaxometry, and MRI.Results: Macrophage uptake of MPIOs was found to be highest for the 1.63-m size particles. MR relaxivity measurements indicated greater spin-spin relaxation for MPIOlabeled cells relative to cells labeled with nanometer-sized ultra-small superparamagnetic iron oxide (USPIO) particles with similar iron content. TEM and fluorescence microscopy indicated cellular uptake of multiple MPIO particles per cell. Macrophages labeled with 1.63-m MPIOs had an average cellular iron uptake of 39.1 pg/cell, corresponding to approximately 35 particles per cell.
Conclusion:Cells labeled with one or more MPIO particles could be readily detected ex vivo at 11.7 Tesla and after infusion of the MPIO-labeled macrophages into the kidney of a rat, hypointense regions of the outer cortex are observed, in vivo, by MRI at 4.7 Tesla.
In the injured central nervous system, myeloid cells, including macrophages and microglia, are key contributors to both myelin injury and repair. This immense plasticity emphasizes the need to further understand the precise molecular mechanisms that contribute to the dynamic regulation of myeloid cell polarization and function. Herein, we demonstrate that miR-223 is upregulated in multiple sclerosis (MS) patient monocytes and the alternativelyactivated and tissue-regenerating M2-polarized human macrophages and microglia. Using miR-223 knock-out mice, we observed that miR-223 is dispensable for maximal proinflammatory responses, but is required for efficient M2-associated phenotype and function, including phagocytosis. Using the lysolecithin animal model, we further demonstrate that miR-223 is required to efficiently clear myelin debris and promote remyelination.These results suggest miR-223 constrains neuroinflammation while also promoting repair, a finding of important pathophysiological relevance to MS as well as other neurodegenerative diseases.
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