Single-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity

Abstract

Knowledge of the transcriptional programs underpinning the functions of human kidney cell populations at homeostasis is limited. We present a single-cell perspective of healthy human kidney from 19 living donors, with equal contribution from males and females, profiling the transcriptome of 27677 cells to map human kidney at high resolution. Sex-based differences in gene expression within proximal tubular cells were observed, specifically, increased anti-oxidant metallothionein genes in females and aerobic metabolism-related genes in males. Functional differences in metabolism were confirmed in proximal tubular cells, with male cells exhibiting higher oxidative phosphorylation and higher levels of energy precursor metabolites. We identified kidney-specific lymphocyte populations with unique transcriptional profiles indicative of kidney-adapted functions. Significant heterogeneity in myeloid cells was observed, with a MRC1+LYVE1+FOLR2+C1QC+ population representing a predominant population in healthy kidney. This study provides a detailed cellular map of healthy human kidney, and explores the complexity of parenchymal and kidney-resident immune cells.

Sex biased human thymic architecture guides T cell development through spatially defined niches

“…Our analysis of thymic cell gene expression uncovers that female-derived stromal, epithelial, and T cells have significant upregulation of metabolic, translation, and antigen presentation pathways whereas male cells have increased adipogenesis, proinflammatory signaling, and glucocorticoid signaling. These differences in cell metabolism align with current literature describing transcript-level sex differences in other organs [41][42][43] and highlight the need for sex-based cell culture optimization to meet differential cell growth and differentiation requirements in in vitro T cell culture systems.…”

“…In addition to these changes common to other organs 40,41 , we identify meaningful thymus-specific differences which could significantly affect key processes in the development and training of thymocytes. Females have a larger proportion of cortical cells per lobule which aligns with known slower rates of thymic involution in females leading to a larger cortex/medulla ratio 26,27,59 .…”

“…Male cells, in contrast, have increased gene expression of adipogenesis, proinflammatory signaling, and glucocorticoid signaling. Nine out the top 10 most differentially expressed pathways we identified for each sex were similarly sex-biased in human kidney 41 , suggesting that multiple cell types show consistent sex-biased enrichment of pathways linked to cellular metabolism, immune responses, and hormone signaling. Indeed, our data correspond closely with sex-based trends identified in human iPSC lines 42 and other human organs 43 , indicating these pathways frequently show differences between male and female cells across many cell types.…”

Sex-biased gene expression across mammalian organ development and evolution

“…Our results suggest that although sexbiased expression evolves fast at the gene level, it evolves more slowly at the cell-type level. This is consistent with a single-cell study of the human kidney (46) that also identified the proximal tubule cells as being sexually dimorphic and driving most sex dimorphisms despite there being very little conservation in the set of sex-biased genes between rodents and humans.…”

Predicting regulators of epithelial cell state through regularized regression analysis of single cell multiomic sequencing

“…Aggregation of these samples yielded 80,634 cells from snRNA-seq and 120,679 cells from snATAC-seq. We could still clearly detect KIM1 +/ VCAM1 + FR proximal tubule cells even when clustering cells solely from living donor kidney biopsies, consistent with recent analysis of living donor kidneys (37), indicating that tumor mass effect alone does not explain FR-PTC accumulation (Figure 1E, Supplemental Figure 3A-D). More broadly, cell type-specific RNA expression and ATAC accessibility profiles were similar between living donor kidney biopsies and nephrectomy samples (Figure 1F, Supplemental Figure 3E).…”