Histological Tracking into the Third Dimension: Evolution of Early Tumorigenesis in VHL Kidney

Using a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis

Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

Abstract Background Inflammation in chronic active lesions occurs behind a closed blood–brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. Objective To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. Methods MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal‐appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human‐induced pluripotent stem cell (iPSC)‐derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro‐inflammatory cytokines. Results QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron− myeloid cells. In vitro, iron accumulation was highest in M1‐polarized human iPSC‐derived microglia, but it did not enhance ROS or cytokine production. Conclusion A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions