Identification of Novel Population-Specific Cell Subsets in Chinese Ulcerative Colitis Patients Using Single-Cell RNA Sequencing

Abstract

Background & Aims Genome-wide association studies (GWAS) and transcriptome analyses have been performed to better understand the pathogenesis of ulcerative colitis (UC). However, current studies mainly focus on European ancestry, highlighting a great need to identify the key genes, pathways and cell types in colonic mucosal cells of adult UC patients from other ancestries. Here we aimed to identify key genes and cell types in colonic mucosal of UC. Methods We performed Single-cell RNA sequencing (scRNA-seq) analysis of 12 colon biopsies of UC patients and healthy controls from Chinese Han ancestry. Results Two novel plasma subsets were identified. Five epithelial/stromal and three immune cell subsets show significant difference in abundance between inflamed and non-inflamed samples. In general, UC risk genes show consistent expression alteration in both Immune cells of inflamed and non-inflamed tissues. As one of the exceptions, IgA defection, marking the signal of immune dysfunction, is specific to the inflamed area. Moreover, Th17 derived activation was observed in both epithelial cell lineage and immune cell lineage of UC patients as compared to controls , suggesting a systemic change of immune activities driven by Th17. The UC risk genes show enrichment in progenitors, glial cells and immune cells, and drug-target genes are differentially expressed in antigen presenting cells. Conclusions Our work identifies novel population-specific plasma cell molecular signatures of UC. The transcriptional signature of UC is shared in immune cells from both inflamed and non-inflamed tissues, whereas the transcriptional response to disease is a local effect only in inflamed epithelial/stromal cells.

Ulcerative Colitis: Novel Epithelial Insights Provided by Single Cell RNA Sequencing

“…Importantly, transcripts elevated in goblet cells ( Figure 2 ) were in agreement with the subsequent study by Li et al ( 35 ), including MUC2, ITLN1, REP15, LRRC26, NPDC1, TPSG1, SERPINA1, CLCA1, and SPINK4.…”

“…In UC-affected epithelium ( Figure 2 ), only SCD, RNASE1, and ASRGL1 were concordant with goblet cell findings by Li et al ( 35 ).…”

“…The expression of potential stem cell-enriched transcripts ( Table 3 ) was not reported in healthy epithelium by Li et al, despite the presence of LGR5 + stem cell clusters in both healthy and UC tissues. In UC, markers elevated in stem cell cluster in either the Oxford or Broad study were discordant with the findings reported by Li et al ( 35 ). EZR, a classical marker of epithelial cells, was found elevated in several epithelial cell clusters, and surprisingly, in fibroblasts.…”

“…Additional scRNA-seq study of colon biopsies from UC patients and healthy controls of Chinese Han ancestry ( 35 ) complemented the Broad and Oxford studies that were conducted in individuals of primarily European ancestry ( 21 , 22 ). In this study, 43,218 cells representing UC-affected sigmoid colon, unaffected proximal colon from UC patients, and sigmoid colon from healthy controls with an average of 1053 genes per cell were mapped into 21 clusters, six of which were epithelial cells (enterocytes, enterocyte progenitors, goblet cells, goblet progenitors, LGR5 + stem cells, and TRPM5 + tuft cells).…”

Single-cell RNA-sequencing combined with bulk RNA-sequencing analysis of peripheral blood reveals the characteristics and key immune cell genes of ulcerative colitis

“…These findings can provide new ideas for the diagnosis and treatment of intestinal diseases[ 7 ]. Li et al [ 8 ] found that UC risk-related genes are enriched in progenitor cells, glial cells and immune cells and showed consistently altered expression in immune cells of both inflammatory and noninflammatory tissues, whereas drug target genes were differentially expressed in antigen-presenting cells. T helper 17 (Th17)-cell activation was observed in both the epithelial cell lineage and immune cell lineage of UC patients, indicating systematic changes in Th17-driven immune activity.…”