Rather than "early," we suggest categorizing by position along the crypt-villus axis. Based on ANPEP expression, we propose the designation "low-to-mid-villus enterocyte." (PMID 28798045)
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Rather than "early," we suggest categorizing by position along the crypt-villus axis. Based on ANPEP expression, we propose the designation "low-to-mid-villus enterocyte." (PMID 28798045)
We recommend merging both goblet cell subclusters. While studies suggest functional heterogeneity within the goblet cell population, it is unclear whether these subpopulations can be distinguished at the transcript level. We also recommend removing the "secretory" prefix — the accepted term is simply "goblet cells."
Considering the previous feedback, the source of the tissue for Goblet Cells is important (splitting between ileum and colon) but from our data, expression of genes such as ZG16 confirm the Goblet Cell phenotype.
This cluster include goblet cells from small intestine and large intestine (split in the UMAP) and mature goblet cells, with high expression of TFF1+. I agree with Ángela Sanzo and I would also split clusters 6 and 11, but also consider splitting cluster 12 (from Leiden lineage 1), and indicate the origin of these cells (small intestine or large intestine)
In our experience, but also seen in other papers (for instance Kong et al), the epithelium is separated by tissue origin (ileum vs colon), hence I would consider this for the analysis. Given that, i think the secretory goblet cells from the ileum in the leiden clustering separates in cluster 6, which might be too mature goblet cells, expression of TFF1 and FERiL6) and cluster 11 would then be the secretory goblet cells found in the ileum
BEST2, KLK3/15, MUC1/2+ --> Secretory goblet cells. See e.g. here: https://www.nature.com/articles/s41586-021-03852-1?utm_source=chatgpt.com
APOB, APOA4, APOC3, SLC* genes suggest enterocyte lineage (Glinka, Wickham and Nadalin et al., 2026, Journal of Pathology)
generally agree, but the cells very close to the secretory goblet cells that still belong to the "early enterocytes" cluster also seem to be quite high for goblet cell markers. MUC2hi, SPINK4, AGR2... Split cluster?
We agree that there is evidence supporting both TA and absorptive lineage identity. Any cluster designated as TA should express cell cycle genes (e.g., MKI67, CDK1), and these should be included in the rationale for naming. Given that the secretory TA designation is itself under debate, designating this cluster as absorptive TA also warrants careful consideration.
We agree with designating late differentiation; we suggest adding AQP8 to the cluster name (PMID 41115527).
High expression of AQP8, indicating top-crypt location and late differentiation
We recommend merging with the general TA cluster. By definition, all TA cells are cycling; separating these populations into two clusters is not functionally meaningful.
In our dataset (PMID 41115527), LEFTY1 was associated with an early progenitor population. There is no functional reason to designate these cells as colonocytes; we recommend merging this cluster with the progenitor population.
We recommend merging with the general TA cluster. By definition, all TA cells are cycling; separating these populations into two clusters is not functionally meaningful.
We agree with this designation and recommend re-labeling as "intestinal stem cells" (the canonical term)
Agree with changing the name to Intestinal Stem Cells. In addition, this cluster is clearly separated in two in the UMAP: small intestinal ISC and colonic ISC. Might it be worth splitting this cluster in two?
Usual nomenclature is Intestinal Stem Cells (ISCs) rather than epithelial. Also I think can remove the "(LGR5+)" as there is not key marker genes in most other cell types
Clear! LGR5+ OLFM5, SMOC2...
A better designation is needed based on current understanding of secretory differentiation. There are no data to support that secretory progenitors undergo transit amplification. We suggest relabeling this cluster as "secretory progenitors."
These cells are colonocytes but lack additional distinguishing features. This cluster appears "smeared" over the UMAP, and a fraction may correspond to what we refer to as FABP1+ colonocytes (PMID 41115527).
We agree with re-naming to BEST4+ colonocytes
These are well-known BEST4+ colonocytes (BEST4, OTOP2) I would just rename them to have the gene before the name.
We agree with this designation and recommend removing the "secretory" prefix.
Tuft cells are secretory per definition. I would just annotate them as "Tuft cells" instead of "Secretory Tuft cells". The same would apply for Goblet cells or Paneth cells.
Expression of TRPM5, SH2D6.... (Garrido-Trigo A)
We recommend removing this cluster. These cells should be excluded during QC prior to publication.
The cells are definitely expressing epithelial gene markers (e.g. MUC) but the clustering is strange.
I think there are some epithelial cells (positive for EPCAM, MUC2...), but part of the cluster are mesenchymal cells and hence the markers that need to be filter out in the QC
Laminin is not typically expressed by colonocytes unless there is underlying pathology. For the annotation phase of a healthy gut atlas, this cluster should not be included as a distinct cell type; it likely represents contamination from IBD or cancer datasets and should be excluded from initial clustering.
Markers LAMA3 and EPHA2 (Garrido-Trigo A)
These are BEST4+ enterocytes (BEST4, OTOP2) I would just reverse name order for consistency (Hickey, J.W et al)
We recommend removing this cluster. Doublets are a technical artifact and should be computationally excluded during quality control rather than retained as a distinct cluster in a published cell atlas.
This should be removed as part of QC as it has the appearance of doublets - expressing epithelial, immune and EEC genes
Mixed cell profile. Some epithelial cells some B cells?
We recommend merging both goblet cell subclusters. While studies suggest functional heterogeneity within the goblet cell population, it is unclear whether these subpopulations can be distinguished at the transcript level. We also recommend removing the "secretory" prefix — the accepted term is simply "goblet cells."
High expression of TFF1, indicating mature state of goblet cells. I would change "Secretory Goblet Cells Mature" to "Goblet cells mature" and indicate whether this cluster is from small intestine or large intestine samples
TNFAIP2+, CCL23+, SOX8+, GP2+ Clear M cells. See also here as reference. https://www.nature.com/articles/s41586-025-09829-8
I agree with separating EEC N cells and Enterochromaffin cells. They correspond to cluster 21 in Leiden_Lineage_L1, but only N cells (small intestine) express NTS. This highlights a major comment in the epithelial subset: it might be helpful to split small intestine and large intestine samples
We recommend removing the "secretory" prefix. The accepted term is simply "Paneth cells."
marker genes DEFA5, DEFA6, REG3A and PLA2G2A (Oliver AJ https://www.nature.com/articles/s41586-024-07571-1)
We recommend removing this cluster from the epithelial atlas. Monocytes are immune cells and do not belong in an annotation framework focused on the intestinal epithelium. They should be represented in a separate immune compartment atlas.
Agree, these are circulating neutrophils (FCGR3B, S100A8...), they may appear on sc of highly vascularized tissues of healthy donors (they only come from 'normal'). Nonetheless, they do not belong in here but in the myeloid compartment.
I think these might be more circulating neutrophils? Definitely myeloid immune cells. CSF3R, FCGR3B, S100A12, SELL... Either way, these cells should be probably deleted from an epithelial cell object.
Enteroendocrine cells refers to a larger cell type resolution. This cells seem to share expression of genes such as NTS with EEC N cell cluster. I would suggest to merge.
We recommend removing this cluster from the epithelial atlas for the same reason as monocytes. Plasma cells are immune cells and their inclusion here likely reflects contamination of the epithelial fraction. They should be represented within the appropriate immune compartment.
Agree to this label. Should be removed from this object as not an epithelial cell but contamination.