Single-cell spatial transcriptomics of formalin-fixed, paraffin-embedded biopsies reveals colitis-associated cell networks
Elvira Mennillo, Madison L. Lotstein, Gyehyun Lee, Julian H. Hou, Vrinda Johri, Donna E. Leet, Christina A. Ekstrand, Jessica Tsui, Jun Yan He, Uma Mahadevan, Walter Eckalbar, Ryan M. Gill, Christopher J. Bowman, David Y. Oh, Gabriela K. Fragiadakis, Michael G. Kattah, Alexis J. Combes
Elvira Mennillo, Madison L. Lotstein, Gyehyun Lee, Julian H. Hou, Vrinda Johri, Donna E. Leet, Christina A. Ekstrand, Jessica Tsui, Jun Yan He, Uma Mahadevan, Walter Eckalbar, Ryan M. Gill, Christopher J. Bowman, David Y. Oh, Gabriela K. Fragiadakis, Michael G. Kattah, Alexis J. Combes
View: Text | PDF
Research Article Gastroenterology Inflammation

Single-cell spatial transcriptomics of formalin-fixed, paraffin-embedded biopsies reveals colitis-associated cell networks

Abstract

Imaging-based, single-cell, spatial transcriptomics (iSCST) of FFPE tissue enables comprehensive analysis of archived specimens while preserving spatial context, critical to an understanding of ulcerative colitis (UC) pathology. Here, we deployed a robust framework for applying iSCST to clinical FFPE mucosal biopsies from patients with UC or immune checkpoint inhibitor–induced colitis, as well as patients serving as healthy controls. iSCST using custom Xenium gene panels enabled precise detection of diverse cell subsets and disease-specific genes. We mapped transcriptionally distinct fibroblast subsets within mucosal niches, including inflammation-associated fibroblasts (IAFs), and identified colitis-specific neighborhoods formed by IAFs, monocytes, and neutrophils. Transcriptional signatures and spatial neighborhoods uncovered through iSCST were associated with vedolizumab (VDZ) response, with nonresponders exhibiting either an innate IAF-monocyte-neutrophil signature or adaptive gut-associated lymphoid tissue signature, while responders showed enrichment of an epithelial cellular neighborhood. These signatures were validated in an internal and an external dataset, supporting the existence of 2 distinct archetypes of treatment resistance to VDZ in UC. This iSCST framework provides a powerful approach for analyzing FFPE tissues, offering insights into colitis-associated cellular networks and identifying biomarkers to enhance patient risk stratification in routine clinical workflows.

Authors

Elvira Mennillo, Madison L. Lotstein, Gyehyun Lee, Julian H. Hou, Vrinda Johri, Donna E. Leet, Christina A. Ekstrand, Jessica Tsui, Jun Yan He, Uma Mahadevan, Walter Eckalbar, Ryan M. Gill, Christopher J. Bowman, David Y. Oh, Gabriela K. Fragiadakis, Michael G. Kattah, Alexis J. Combes

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

Supplemental data - Download (20.79 MB)

Advertisement