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. 2024 Feb 14;22(1):36.
doi: 10.1186/s12915-024-01812-5.

A human stomach cell type transcriptome atlas

S Öling  1 , E Struck  1 , M Noreen-Thorsen  1 , M Zwahlen  2 , K von Feilitzen  2 , J Odeberg  1   2   3   4 , F Pontén  5 , C Lindskog  5 , M Uhlén  2 , P Dusart  2   6   7 , L M Butler  8   9   10   11
Affiliations

A human stomach cell type transcriptome atlas

S Öling et al. BMC Biol. .

Abstract

Background: The identification of cell type-specific genes and their modification under different conditions is central to our understanding of human health and disease. The stomach, a hollow organ in the upper gastrointestinal tract, provides an acidic environment that contributes to microbial defence and facilitates the activity of secreted digestive enzymes to process food and nutrients into chyme. In contrast to other sections of the gastrointestinal tract, detailed descriptions of cell type gene enrichment profiles in the stomach are absent from the major single-cell sequencing-based atlases.

Results: Here, we use an integrative correlation analysis method to predict human stomach cell type transcriptome signatures using unfractionated stomach RNAseq data from 359 individuals. We profile parietal, chief, gastric mucous, gastric enteroendocrine, mitotic, endothelial, fibroblast, macrophage, neutrophil, T-cell, and plasma cells, identifying over 1600 cell type-enriched genes.

Conclusions: We uncover the cell type expression profile of several non-coding genes strongly associated with the progression of gastric cancer and, using a sex-based subset analysis, uncover a panel of male-only chief cell-enriched genes. This study provides a roadmap to further understand human stomach biology.

Keywords: Bulk RNAseq; Cell profiling; Gene enrichment; Stomach.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Integrative co-expression analysis can resolve constituent cell type identities from unfractionated human stomach tissue RNAseq data. (A) RNAseq data for 359 unfractionated human stomach samples were retrieved from GTEx V8. Each sample contained (i) mixed cell types, which contributed (ii) differing proportions of sequenced mRNA. (B) To profile cell type-enriched transcriptomes, constituent cell types were identified and candidate marker genes (´reference transcripts´ [Ref.T.]) for virtual tagging of each were selected, based on in house tissue protein profiling and/or existing literature and datasets. (C) Matrix of correlation coefficients between selected Ref.T. across the sample set. (D) Mean correlation coefficients of genes above designated thresholds for classification as cell-type enriched in stomach: (i) parietal cells [PC], (ii) chief cells [CC], (iii) gastric enteroendocrine cells [GEEC], (iv) gastric mucous cells [GMC], (v) mitotic cells [MTC], (vi) endothelial cells [EC], (vii) fibroblasts [FB], (viii) macrophages [MC], (ix) neutrophils [NP], (x) T-cells [TC], (xi) plasma cells [PC] with all Ref.T. panels. (E) Over-represented gene ontology terms among genes predicted to be: (i) endothelial cell, (ii) fibroblast or (iii) T-cell enriched. (F) Principal component analysis of correlation profiles of cell type enriched genes. See also Table S1 Tab 1 and 2 and Figure S1 for method overview
Fig. 2
Fig. 2
Integrative co-expression analysis of unfractionated RNAseq reveals enriched genes in human stomach cell types. (A) Total number and proportional representation of class for cell type enriched genes in: (i) gastric mucous cells, (ii) plasma cells, (iii) fibroblasts, (iv) mitotic cells, (v) macrophages, (vi) parietal cells, (vii) chief cells, (viii) endothelial cells, (ix) gastric enteroendocrine cells, (x) T-cells and (xi) neutrophils. (cells, (viii) endothelial cells, (ix) gastric enteroendocrine cells, (x) T-cells and (xi) neutrophils. (B) RNAseq data for) RNAseq data for 359 unfractionated human stomach samples was subject to weighted correlation network analysis (WGCNA). (i) Coloured squares indicate cell type Ref.T. positions on resultant dendrogram. (ii) Coloured bars show distribution of protein coding genes classified as cell type-enriched across dendrogram groups. (C) Human stomach tissue profiling for proteins encoded by genes classified as: (i) gastric enteroendocrine cell, (ii) mitotic cell, (iii) parietal cell, (iv) chief cell or (v) gastric mucous cell enriched. (D) Over-represented gene ontology terms among genes predicted to be (i) gastric enteroendocrine cell, (ii) parietal cell or (iii) gastric mucous cell enriched. See also Table S1 Tab 2, 3, 5 and 6
Fig. 3
Fig. 3
Protein coding gene signatures of human stomach cell types. Cell type-enriched protein coding genes in: (A) parietal cells, (B) chief cells, (C) gastric enteroendocrine cells, (D) gastric mucous cells, (E) mitotic cells, (F) endothelial cells, (G) fibroblasts, (H) macrophages, (I) neutrophils (J) T-cells and (K) plasma cells, showing: (i) differential correlation score (correlation with cell type Ref.T., panel minus max correlation with any other Ref.T. panel) and mean expression in bulk RNAseq. (ii) Human stomach tissue protein profiling for selected cell type enriched genes. See also Table S1 Tab 2
Fig. 4
Fig. 4
Gastric mucous cells, parietal cells and chief cells are the primary source of stomach tissue enriched genes. (A) The top 200 stomach enriched genes (vs. other tissue types) in RNAseq data from the GTEx Portal or Human Protein Atlas (HPA) were compared to identify genes common to both datasets (n=78). For each, the following was plotted: (B) (i) the mean correlation with each cell type Ref.T. panel, and (ii) the differential value vs. the next most highly correlating Ref.T. panel (dotted line indicates threshold for classification as cell type enriched). Enlarged circles represent genes with predicted cell type enrichment
Fig. 5
Fig. 5
Non-coding gene signatures of human stomach cell types. (A) Heat map of non-coding genes predicted to be cell type enriched, showing differential score between mean correlation coefficient with the corresponding Ref.T. panel vs. highest mean correlation coefficient amongst the other Ref.T. panels. (B) RNAseq data for 359 unfractionated human stomach samples was subject to weighted correlation network analysis (WGCNA). (i) Coloured squares indicate cell type Ref.T. positions on resultant dendrogram. (ii) Coloured bars show distribution of non-coding genes classified as cell type-enriched across dendrogram groups. Non-coding gene enrichment signatures for: (C) gastric enteroendocrine cells, (D) gastric mucous cells and (E) endothelial cells, detailing: (i) up to 25 examples of cell type enriched non-coding genes, ordered by correlation coefficient with the Ref.T. panel, showing differential correlation scores (correlation with corresponding cell type Ref.T., panel minus max correlation with any other Ref.T. panel), mean expression in bulk RNAseq and transcript type. (ii and iii) scRNAseq data from analysis of epithelial, endothelial, immune or stromal cell compartments across 24 human tissues was sourced from Tabula Sapiens (Tabula Sapiens et al., [7]), and used to generate UMAP plots showing the expression profiles of example cell type enriched non-coding genes. The largest plot shows the compartment with the highest expression. See also Table S1 Tab 2 and Figure S3 (for all UMAP plot annotations)
Fig. 6
Fig. 6
Core non-coding gene signatures of human stomach cell types and tissue distribution patterns. Non-coding gene enrichment signatures for: (A) parietal cells, (B) chief cells, (C) plasma cells and (D) endothelial cells, detailing (i) up to 25 examples of cell type enriched non-coding genes, ordered by correlation coefficient with the Ref.T. panel, showing differential correlation scores (correlation with corresponding cell type Ref.T., panel minus max correlation with any other Ref.T. panel), mean expression in bulk RNAseq and gene type. (ii and iii) scRNAseq data from analysis of epithelial, endothelial, immune, or stromal cell compartments across 24 human tissues was sourced from Tabula Sapiens (Tabula Sapiens et al., 2022), and used to generate UMAP plots showing the expression profiles of example cell type enriched non-coding genes. The largest plot shows the compartment with the highest expression. (E) The most highly expressed cell type enriched non‐coding genes in stomach bulk RNAseq. (F) Expression of genes classified as enriched in parietal cells: (i) LINC00982 and (ii) PP7080, plasma cells: (iii) IGLC6, gastric mucous cells: (vi) FER1L4 and (v) RP11-363E7.4, fibroblasts: (vi) HSPA7 and chief cells: (vii) C9orf147, in bulk RNAseq of different human organs. Mean TMP expression is annotated for selected organs on each plot. See also Table S1 Tab 2 and Figure S2 (for all UMAP plot annotations)
Fig. 7
Fig. 7
Identification of sex-specific cell-enriched genes in human stomach tissue. (A) Human stomach RNAseq data (n=359 individuals) was retrieved from GTEx V8 and divided into female (n=132) and male (n=227) subgroups before classification of cell type-enriched genes. For genes classified as: (i) parietal, (ii) gastric mucous, (iii) gastric enteroendocrine or (vi) chief cell enriched in either sex, the ´sex differential corr. score’ (difference between mean corr. with the Ref.T. panel in females vs. males) was plotted vs. ‘enrichment score´ (position in each respective enriched list, highest score = highest corr.). On each plot, genes enriched in both females and males are represented by common-coloured square symbols, and genes classified as enriched only in females or males are represented by differently coloured circle and triangle symbols, respectively. (B) Expression in female or male samples for genes classified as male-only enriched in chief cells: (i) ARSFP1, (iii) TBL1Y and (iii) RP11-115H13.1. (C) scRNAseq data from analysis of epithelial, endothelial, immune or stromal cell compartments across human tissues from male donors was sourced from Tabula Sapiens (Tabula Sapiens et al., [7]), and used to generate UMAP plots showing the expression profiles of: (i) ARSFP1, (iii) TBL1Y and (iii) RP11-115H13.1. (D) Expression of: (i) ARSFP1, (iii) TBL1Y and (iii) RP11-115H13.1 in bulk RNAseq of different human organs from male donors. The largest plot shows the compartment with the highest expression. Mean expression is annotated for selected organs on each plot. See also Table S2 Tab 1, Figure S2 (for all UMAP plot annotations) and Figure S3
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