Single-cell RNA sequencing reveals the role of cell heterogeneity in the sex difference in primary hyperparathyroidism

ObjectiveTo explore the difference in parathyroid tissue-derived cells between male and female PHPT patients. MethodsResected parathyroid tissues were collected from PHPT patients of both sexes. Single cells were isolated and sequenced for RNA expression profiles. The cell sequencing data were annotated by cell type, followed by population analysis, functional analysis, pathway analysis, cell communication analysis, differential gene expression analysis, and pseudotime trajectory analysis. The subcluster analyses were also performed in the parathyroid cells. ResultsNo substantial difference in the cell population, function, or communication is found between the two sexes. The interferon-a response, oxidative phosphorylation, and reactive oxygen species pathways are up-regulated in females than in male patients, mainly contributed by fibroblast cells, endothelial cells, parathyroid cells, and myeloid cells, which also have significantly more up-regulated pathways and cellular interactions than the other three cell types. The subcluster analysis of parathyroid cells identified five subpopulations: SPARCL1-OC and ISG15-OC are predominant in females, while more S100A13-PCC and PTHLH-OC are found in males. The cellular functions are also elevated in females compared with males. Cells from female patients show a higher expression level of parathyroid hormone (PTH) but a lower expression level of parathyroid hormone-like hormone (PTHLH). The cell pseudotime trajectory and pathway analyses show that the oxyphil cells may be more mature and functionally active than the chief cells in both sexes. ConclusionThese findings suggest that the sex difference in PHPT may be caused by the differentially expressed genes and activated pathways in different cell types in the parathyroid tissue. The heterogeneity of parathyroid cell subpopulations, especially in oxyphil cells, may be associated with the sex differences in PHPT pathogenesis.

Automated summary

This study explored the differences in parathyroid tissue-derived cells between male and female patients with primary hyperparathyroidism (PHPT). The results showed that there was no substantial difference in cell population, function, or communication between the two sexes. However, in female patients, pathways and cellular interactions were up-regulated in fibroblast cells, endothelial cells, parathyroid cells, and myeloid cells. Subcluster analysis of parathyroid cells identified different subpopulations in males and females. Cellular functions were also elevated in females compared to males. The findings suggest that sex differences in PHPT may be caused by differentially expressed genes and activated pathways in different cell types in the parathyroid tissue.