Single-cell transcriptomics provides new insights into the role of fibroblasts during peritoneal fibrosis

Background: The contributions of various types of cell populations in dialysis-related peritoneal fibrosis are poorly understood. Single-cell RNA sequencing brings single-cell level resolution to the analysis of cellular transcriptomics, which provides a new way to further characterize the distinct roles and functional states of each cell population during peritoneal fibrosis.

Methods: Single-cell transcriptomics from normal peritoneal tissues of six patients, from effluent of patients with short-term peritoneal dialysis (less than 2 weeks, n = 6), and from long-term peritoneal dialysis patients (more than 6 years, n = 4) were analyzed.

Results: We identified a distinct cell component between samples among different groups. Functional analysis of the differentially expressed genes identified cell type specific biological processes relevant to different fibrosis stages. Well-known key molecular mechanisms participating in the pathophysiology of peritoneal fibrosis were vitrified, and some of them were found to be restricted to specific cell types. Gradually growing enrichment of PI3K/AKT/mTOR pathway and impairment of oxidative phosphorylation in mesothelial cells and fibroblasts were found from healthy control, short-term dialysis, to long-term dialysis, respectively. The fibroblasts' population obtained from the patients, who received peritoneal dialysis, showed a functional characteristic of immune-chemotaxis and immune response, which was characterized by broadly significant increase in the expression of interleukins, chemokines, cytokines, and human leukocyte antigens. Furthermore, we described the intercellular crosstalk networks based on receptor-ligand interactions, and highlighted a central role of fibroblasts in regulating the key mechanisms of peritoneal fibrosis through crosstalk with other cells.

Conclusions: In summary, despite describing information for fibrogenic molecular mechanisms in the resolution level of individual cell populations, this work identifies the significant functional evolution of fibroblasts during peritoneal fibrosis. This study also reveals the intercellular receptor-ligand interactions in which the fibroblasts serve as a major node, eventually providing new insights into the role of fibroblasts during disease pathogenesis.