Understanding the Foreign Body Response via Single-Cell Meta-Analysis.

Simple Summary: When a medical implant or electrode is placed, the body often evokes an immune response in an attempt to remove it. As it fails to do so, this inflammatory response leads to a chronic fibrosis, wherein the material is walled off from the body with scar tissue. This phenomenon is known as foreign body response (FBR) and poses a significant burden, as it often impacts the implant's function and longevity. Single-cell RNA sequencing (scRNA-seq), a technique evaluating the genes transcribed at a single-cell level within a given sample, has been used to identify targets to reduce the extent of fibrosis caused by FBR. We performed a meta-analysis collecting all available FBR mouse scRNA-seq studies to identify gene signatures specific to FBR across different models and anatomic locations. Through our integrated analysis, we identified specific groups of fibroblasts and macrophages associated with FBR, characterizing their associated genes and signaling pathways. Fibroblasts enriched in FBR had increased pro-fibrotic signatures, while macrophages enriched in FBR had both increased pro-fibrotic and pro-inflammatory profiles. Collectively, our meta-analysis identifies common cell-specific gene signatures in FBR and provides potential therapeutic targets for patients requiring long-term implanted biomedical devices. Foreign body response (FBR) is a universal reaction to implanted biomaterial that can affect the function and longevity of the implant. A few studies have attempted to identify targets for treating FBR through the use of single-cell RNA sequencing (scRNA-seq), though the generalizability of these findings from an individual study may be limited. In our study, we perform a meta-analysis of scRNA-seq data from all available FBR mouse studies and integrate these data to identify gene signatures specific to FBR across different models and anatomic locations. We identify subclusters of fibroblasts and macrophages that emerge in response to foreign bodies and characterize their signaling pathways, gene ontology terms, and downstream mediators. The fibroblast subpopulations enriched in the setting of FBR demonstrated significant signaling interactions in the transforming growth factor-beta (TGF-β) signaling pathway, with known pro-fibrotic mediators identified as top expressed genes in these FBR-derived fibroblasts. In contrast, FBR-enriched macrophage subclusters highly expressed pro-fibrotic and pro-inflammatory mediators downstream of tumor necrosis factor (TNF) signaling. Cell–cell interactions were additionally interrogated using CellChat, with identification of key signaling interactions enriched between fibroblasts and macrophages in FBR. By combining multiple FBR datasets, our meta-analysis study identifies common cell-specific gene signatures enriched in foreign body reactions, providing potential therapeutic targets for patients requiring medical implants across a myriad of devices and indications. [ABSTRACT FROM AUTHOR]