Complexity of Secretory Chemokines in Human Intestinal Organoid Cultures Ex Vivo

Cottle, Chasen; Anbazhagan, Murugadas; Lipat, Ariel Joy; Patel, Mital D.; Porter, Amanda Paige; Hogan, Keenan; Rajan, Devi; Matthews, Jonathan; Kugathasan, Subra; Chinnadurai, Raghavan

doi:10.1016/j.gastha.2022.02.009

Cited by 4 publications

(4 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that a candidate moment to prevent T cell migration by targeting CXCL11 would be in the initial phases of inflammation. Indeed, organoids generated from IBD patients do not express higher CXCL11 than controls, suggesting that the upregulation of this chemokine is reversible outside of the inflammatory microenvironment even from patients exposed to long-term immune-mediated intestinal injury 55 . An important consideration is that T regulatory (T reg ) cells counteract pro-inflammatory stimuli and can also traffic through chemokine gradients sensed by CXCR3 56 .…”

Section: Discussionmentioning

confidence: 99%

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

Cutilli,

Jansen,

Paolucci

et al. 2024

Preprint

View full text Add to dashboard Cite

The cytokine interferon-gamma (IFNγ) plays a multifaceted role in intestinal immune responses ranging from anti-to pro-inflammatory depending on the setting. Here, using a 3D co-culture system based on human intestinal epithelial organoids, we explore the capacity of IFNγ-exposure to reprogram intestinal epithelia and thereby directly modulate lymphocyte responses. IFNγ treatment of organoids led to transcriptional reprogramming, marked by a switch to a pro-inflammatory gene expression profile, including transcriptional upregulation of the chemokines CXCL9, CXCL10, and CXCL11. Proteomic analysis of organoid-conditioned medium post-treatment confirmed chemokine secretion. Furthermore, IFNγ-treatment of organoids led to enhanced T cell migration in a CXCL11-dependent manner without affecting T cell activation status. Taken together, our results suggest a specific role for CXCL11 in T cell recruitment that can be targeted to prevent T cell trafficking to the inflamed intestine.

show abstract

Section: Discussionmentioning

confidence: 99%

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

Cutilli,

Jansen,

Paolucci

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Recent work from our group using patient-derived intestinal organoids has begun to show the importance of the epithelium in CD and its role in producing soluble molecules that can impact the behavior of surrounding cell types, including those in the immune compartment. 5 , 37 Studies of Kaser et al 38 and Smillie et al 20 showed that the CCR6 receptor and its ligand CCL20 were upregulated in both CD and UC in 114 patients and is a GWAS-implicated risk gene 20 for UC. Furthermore, our analysis showed that epithelial subclusters such as enterocytes, M cells, and TA/undifferentiated cells had significant increases in HLA-DP , HLA-DR , and HLA-B in CD patients with a fold change >2.…”

Section: Discussionmentioning

confidence: 99%

Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naïve and Treated Crohn’s Disease

Maddipatla

Kolachala

Venkateswaran

et al. 2022

Inflammatory Bowel Diseases

View full text Add to dashboard Cite

Background Crohn’s disease is a lifelong disease characterized by chronic inflammation of the gastrointestinal tract. Defining the cellular and transcriptional composition of the mucosa at different stages of disease progression is needed for personalized therapy in Crohn’s. Methods Ileal biopsies were obtained from (1) control subjects (n = 6), (2) treatment-naïve patients (n = 7), and (3) established (n = 14) Crohn’s patients along with remission (n = 3) and refractory (n = 11) treatment groups. The biopsies processed using 10x Genomics single cell 5' yielded 139 906 cells. Gene expression count matrices of all samples were analyzed by reciprocal principal component integration, followed by clustering analysis. Manual annotations of the clusters were performed using canonical gene markers. Cell type proportions, differential expression analysis, and gene ontology enrichment were carried out for each cell type. Results We identified 3 cellular compartments with 9 epithelial, 1 stromal, and 5 immune cell subtypes. We observed differences in the cellular composition between control, treatment-naïve, and established groups, with the significant changes in the epithelial subtypes of the treatment-naïve patients, including microfold, tuft, goblet, enterocyte,s and BEST4+ cells. Surprisingly, fewer changes in the composition of the immune compartment were observed; however, gene expression in the epithelial and immune compartment was different between Crohn’s phenotypes, indicating changes in cellular activity. Conclusions Our study identified cellular and transcriptional signatures associated with treatment-naïve Crohn’s disease that collectively point to dysfunction of the intestinal barrier with an increase in inflammatory cellular activity. Our analysis also highlights the heterogeneity among patients within the same disease phenotype, shining a new light on personalized treatment responses and strategies.

show abstract

“…In support of this new hypothesis, our analysis showed higher levels of a well-studied IBD chemokine CCL20 in M-cells of TN_CD and found increases in CCL5 production in T- and NK cells. Recent work from our group using patient derived intestinal organoids has begun to show the importance of the epithelium in CD and its role in producing soluble molecules that can impact the behavior of surrounding cell types including those in the immune compartment 7, 51 . Studies of Kaser et., al 52 and Smillie et.…”

Section: Discussionmentioning

confidence: 99%

Assessing Cellular and Transcriptional diversity of IIeal Mucosa amongst Treatment Naïve and Treated Crohn’s disease

Maddipatla

Kolachala

Venkateswaran

et al. 2022

Preprint

View full text Add to dashboard Cite

Background and Aims: Crohns disease is a life-long disease characterized by chronic inflammation of the gastrointestinal tract. Defining the cellular and transcriptional composition of the mucosa at different stages of disease progression is needed for personalized therapy in Crohns. Methods: Ileal biopsies were obtained from (i) controls (n=6), (ii) treatment naive (n=7), and (iii) established (n=14) Crohns patients along with remission (n=3) and refractory (n=11) treatment groups. The biopsies were processed using 10x Genomics single cell 5 yielded 139,906 cells. Gene expression count matrices of all samples were analyzed by reciprocal principal component integration, followed by clustering analysis. Manual annotations of the clusters were performed using canonical gene markers. Cell type proportions, differential expression analysis and gene ontology enrichment were carried out for each cell type. Results: We identified 3 cellular compartments with 9 epithelial, 1 stromal, and 5 immune cell subtypes. We observed differences in the cellular composition between ctrl, treatment naive and established groups, with the significant changes in the epithelial subtypes of the treatment-naive patients, including microfold, tuft, goblet, enterocytes and BEST4+ cells. Surprisingly, fewer changes in the composition of the immune compartment were observed, however gene expression in the epithelial and immune compartment was different between Crohns phenotypes indicating changes in cellular activity. Conclusions: Our study identified cellular and transcriptional signatures associated with treatment naive that collectively points to dysfunction of the intestinal barrier with an increase in inflammatory cellular activity. Our analysis also highlights the heterogeneity amongst patients within the same disease phenotype, shinning new light on personalized treatment responses and strategies.

show abstract

Complexity of Secretory Chemokines in Human Intestinal Organoid Cultures Ex Vivo

Cited by 4 publications

References 9 publications

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naïve and Treated Crohn’s Disease

Assessing Cellular and Transcriptional diversity of IIeal Mucosa amongst Treatment Naïve and Treated Crohn’s disease

Contact Info

Product

Resources

About