Cell Simulation as Cell Segmentation.

Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render this data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation to rapidly infer morphologically plausible cell boundaries that preserve cell type heterogeneity. Benchmarking applied to datasets generated by three commercial platforms show superior performance and computational efficiency of this approach compared with existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult to accurately segment tumor infiltrating immune cells such as neutrophils and T cells. Lastly, through improvements in our ability to delineate subsets of tumor infiltrating T cells, we show that CXCL13-expressing CD8+ T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from renal cell carcinoma patient samples. Proseg is available under at open source license at https://github.com/dcjones/proseg.

Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer.

Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal via the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified in vivo. By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady-state microglia, Langerhans cells, and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34 was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during Listeria infection reveals no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage-driven immune-pathologies.