Biology subjects

Diaz, O. E.

Publications and source records attributed to Diaz, O. E..

3 recordsLinked to original sources

bioRxiv2025

Cell heterogeneity and fate bistability drive tissue patterning during intestinal regeneration

Tissue regeneration relies on the ability of cells to undergo de novo patterning. While tissue patterning has been viewed as the transition from initially identical un-patterned cells to an arrangement of different cell types, recent evidence suggests that initial heterogeneities between cells modulate tissue-scale pattern formation. Yet, how such heterogeneities arise and, thereafter, regulate cell type emergence in a population of cells is poorly understood. Using in vivo and in vitro mouse regenerative systems, we identify a critical tissue density that is required to induce heterogeneous inactivation of the mechanosensor YAP1. Experimental and biophysical approaches demonstrate that YAP1 cell-to-cell heterogeneity pre-patterns the first cell fate decision, via both chromatin remodelling and a supracellular feedback between FOXA1 and Delta-Notch signalling. This feedback motif induces cell fate bistability endowing memory to the system and the maintenance of patterns during homeostasis. These findings reveal a generalisable framework in which transient cell-to-cell heterogeneity, regulated by tissue-scale properties, serves as a critical control parameter for the emergence of cell fate and stable patterning during regeneration.

cell biology↗

bioRxiv2020

Lysophosphatidic acid-mediated GPR35 signaling in CX3CR1+ macrophages regulates the intestinal cytokine milieu

Single nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, the mechanism(s) by which GPR35 modulates the intestinal milieu remain undefined. Here we demonstrate in zebrafish and mice that expression of Gpr35 is microbiota-dependent and is enhanced upon inflammation. We identify a GPR35+ colonic macrophage population in mice that is characterized by increased production of pro-inflammatory cytokines, and determine that lysophosphatidic acid (LPA) acts as an endogenous GPR35 ligand to induce Tnf expression. Mice lacking Gpr35 in CX3CR1+ macrophages have aggravated colitis when exposed to dextran sodium sulfate, have decreased transcript levels of the corticosterone-generating gene Cyp11b1, and reduced levels of macrophage-derived TNF. Administration of TNF in these mice restores Cyp11b1 expression and intestinal corticosterone production, and ameliorates DSS-induced colitis. These findings suggest that LPA signals through GPR35 in CX3CR1+ macrophages to control the intestinal cytokine milieu. HighlightsO_LIInflammatory cues and the microbiota modulate Gpr35 expression across species C_LIO_LILPA modulates GPR35-dependent functions in zebrafish and mice macrophages C_LIO_LIGPR35 expressing macrophages have a protective role during intestinal inflammation C_LIO_LIGPR35 control intestinal inflammation by inducing TNF and corticosterone synthesis C_LI eTOC BlurbGPR35 have been associated with IBD, but how GPR35 may influence macrophage-mediated intestinal homeostasis remains unclear. Using zebrafish and mice genetic tools, Niess, Villablanca, and colleagues have identified that LPA triggers GPR35 activity, and loss of macrophage GPR35 signaling confers intrinsic dysfunctions with effects on cytokine production and intestinal homeostasis.

immunology↗

bioRxiv2019

Conserved transcriptomic profile between mouse and human colitis allows temporal dynamic visualization of IBD-risk genes and unsupervised patient stratification

AbstrasctDespite the fact that ulcerative colitis (UC) patients show heterogeneous clinical manifestation and diverse response to biological therapies, all UC patients are classified as one group. Therefore, there is a lack of tailored therapies. In order to design these, an unsupervised molecular re-classification of UC patients is evoked. Classical clustering approaches based on tissue transcriptomic data were not able to classify UC patients into subgroups, likely due to associated covariates. In addition, while genome wide association studies (GWAS) have identified potential new target genes, their temporal dynamic revealing the optimal therapeutic window of time remains to be elucidated. To overcome the limitations, we generated time-series transcriptome data from a mouse model of colitis, which was then cross-compared with human datasets. This allowed us to visualize IBD-risk gene expression kinetics and reveal that the expression of the majority of IBD-risk genes peak during the inflammatory phase, and not the recovery phase. Moreover, by restricting the analysis to the most differentially expressed genes shared between mouse and human, we were able to cluster UC patients into two subgroups, termed UC1 and UC2. We found that UC1 patients expressed higher copy of genes involved in neutrophil recruitment, activation and degranulation compared to UC2. Of note, we found that over 87% of UC1 patients failed to respond to two of the most widely-used biological therapies for UC.\n\nThis study serves as a proof of concept that cross-species comparison of gene expression profiles enables the temporal annotation of disease-associated gene expression and the stratification of patients as of yet considered molecularly undistinguishable.

immunology↗